US20210345916A1 - Silicone based membranes for use in implantable glucose sensors - Google Patents
Silicone based membranes for use in implantable glucose sensors Download PDFInfo
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- US20210345916A1 US20210345916A1 US17/330,265 US202117330265A US2021345916A1 US 20210345916 A1 US20210345916 A1 US 20210345916A1 US 202117330265 A US202117330265 A US 202117330265A US 2021345916 A1 US2021345916 A1 US 2021345916A1
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- glucose
- membrane
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/6848—Needles
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
- C08L83/04—Polysiloxanes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y70/00—Materials specially adapted for additive manufacturing
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/12—Polysiloxanes containing silicon bound to hydrogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/20—Polysiloxanes containing silicon bound to unsaturated aliphatic groups
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/42—Block-or graft-polymers containing polysiloxane sequences
- C08G77/46—Block-or graft-polymers containing polysiloxane sequences containing polyether sequences
Definitions
- the invention relates to membranes for use in implantable analyte sensors (e.g., glucose sensors).
- implantable analyte sensors e.g., glucose sensors
- Electrochemical sensors are useful in chemistry and medicine to determine the presence or concentration of a biological analyte. Such sensors are useful, for example, to monitor glucose in diabetic patients and lactate during critical care events.
- Diabetes mellitus is a disorder in which the pancreas cannot create sufficient insulin (Type I or insulin dependent) and/or in which insulin is not effective (Type 2 or non-insulin dependent).
- Type I or insulin dependent in which the pancreas cannot create sufficient insulin
- Type 2 or non-insulin dependent in which insulin is not effective
- a hypoglycemic reaction low blood sugar is induced by an inadvertent overdose of insulin, or after a normal dose of insulin or glucose-lowering agent accompanied by extraordinary exercise or insufficient food intake.
- SMBG self-monitoring blood glucose
- transdermal and implantable electrochemical sensors are being developed for continuously detecting and/or quantifying blood glucose values.
- Many implantable glucose sensors suffer from complications within the body and provide only short-term or less-than-accurate sensing of blood glucose.
- transdermal sensors have problems in accurately sensing and reporting back glucose values continuously over extended periods of time.
- One embodiment disclosed herein includes a membrane for use in an analyte sensor, the membrane including a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer, wherein the membrane is adapted to permit diffusion of both the analyte and oxygen therethrough.
- the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer.
- the silicone elastomer comprises vinyl substituents.
- the silicone elastomer is an elastomer produced by curing a MED-4840 mixture.
- the copolymer comprises hydroxy substituents.
- the co-polymer is a triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In one embodiment, the co-polymer is a triblock poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In one embodiment, the co-polymer is a PLURONIC® polymer. In one embodiment, the co-polymer is PLURONIC® F-127. In one embodiment, the analyte is glucose. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of the membrane is the co-polymer.
- an implantable analyte sensor having an enzyme layer comprising an enzyme for which the analyte is a substrate and a bioprotective layer positioned between the enzyme layer and tissue adjacent to the sensor when implanted, wherein the bioprotective layer comprises a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer.
- the bioprotective layer comprises a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer.
- One embodiment further includes a diffusion resistance layer positioned between the enzyme layer and the bioprotective layer.
- the diffusion resistance layer also comprises the silicone elastomer and the poly(ethylene oxide) and poly(propylene oxide) co-polymer.
- the ratio of the silicone elastomer to the co-polymer is different in the diffusion resistance layer than in the bioprotective layer.
- One embodiment further includes a cell disruptive layer positioned between the bioprotective layer and tissue adjacent to the sensor when implanted.
- the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer.
- the silicone elastomer comprises vinyl substituents.
- the silicone elastomer is an elastomer produced by curing a MED-4840 mixture.
- the copolymer comprises hydroxy substituents.
- the co-polymer is a triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In one embodiment, the co-polymer is a triblock poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In one embodiment, the co-polymer is a PLURONIC® polymer. In one embodiment, the co-polymer is PLURONIC® F-127. In one embodiment, the analyte is glucose. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of the bioprotective layer is the co-polymer.
- the enzyme layer also comprises the silicone elastomer and the co-polymer. In one embodiment, the ratio of the silicone elastomer to the co-polymer is different in the enzyme layer than in the bioprotective layer.
- the sensor is configured to be wholly implanted. In one embodiment, the sensor is configured to be transcutaneously implanted. In one embodiment, at least a portion of the bioprotective layer is porous and adjacent to tissue when implanted.
- an implantable analyte sensor having an enzyme layer comprising an enzyme for which the analyte is a substrate and a diffusion resistance layer comprising a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer, wherein the diffusion resistance layer is positioned between the enzyme layer and tissue adjacent to the sensor when implanted.
- a bioprotective layer positioned between the diffusion resistance layer and tissue adjacent to the sensor when implanted.
- the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer.
- the silicone elastomer comprises vinyl substituents.
- the silicone elastomer is an elastomer produced by curing a MED-4840 mixture.
- the copolymer comprises hydroxy substituents.
- the co-polymer is a PLURONIC® polymer.
- the co-polymer is PLURONIC® F-127.
- the analyte is glucose.
- at least a portion of the co-polymer is cross-linked.
- from about 5% w/w to about 30% w/w of the diffusion resistance layer is the co-polymer.
- the ratio of the silicone elastomer to co-polymer varies within the diffusion resistance layer.
- the sensor is configured to be wholly implanted. In one embodiment, the sensor is configured to be transcutaneously implanted.
- an implantable analyte sensor having at least one polymer membrane, wherein every polymer membrane in the sensor comprises a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer.
- the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer.
- the silicone elastomer comprises vinyl substituents.
- the silicone elastomer is an elastomer produced by curing a MED-4840 mixture.
- the copolymer comprises hydroxy substituents.
- the co-polymer is a PLURONIC® polymer.
- the co-polymer is PLURONIC® F-127. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of each polymer membrane is the co-polymer. In one embodiment, the sensor comprises at least two polymer membranes having a ratio of the silicone elastomer to the co-polymer that is different. In one embodiment, the sensor is configured to be wholly implanted. In one embodiment, the sensor is configured to be transcutaneously implanted.
- Another embodiment disclosed herein includes a method of manufacturing a membrane for use in an analyte sensor, the method including mixing a precursor of a silicone elastomer with a poly(ethylene oxide) and poly(propylene oxide) co-polymer and heating the mixture.
- the ratio of co-polymer to silicone elastomer that is mixed is from about 1:20 w/w to about 1:4 w/w.
- One embodiment further includes mixing the co-polymer with a cross-linking agent.
- the cross-linking agent is mixed with the co-polymer prior to mixing the co-polymer with the silicone elastomer precursor.
- the cross-linking agent is selected from the group consisting of one or more of ethylene glycol diglycidyl ether and poly(ethylene glycol) diglycidyl ether. In one embodiment, the cross-linking agent comprises dicumyl peroxide. In one embodiment, the ratio of cross-linking agent to co-polymer is from about 10 cross-linking agent molecules per co-polymer molecule to about 30 cross-linking agent molecules per co-polymer molecule. In one embodiment, the amount of cross-linking agent added relative to the silicone elastomer and co-polymer is from about 0.5% to about 15% w/w. One embodiment further includes, after the mixing step but before the heating step, drawing the mixture into a thin film. One embodiment further includes, after the drawing step but before the heating step, placing a piece of porous silicon on the thin film.
- FIG. 1 is an exploded perspective view of an implantable glucose sensor in one exemplary embodiment.
- FIG. 2 is a block diagram that illustrates the sensor electronics in one embodiment; however a variety of sensor electronics configurations can be implemented with the preferred embodiments.
- FIG. 3 is a perspective view of a transcutaneous wire analyte sensor system.
- FIG. 4 is a schematic illustration of a membrane system of the device of FIG. 1 .
- FIG. 5 is a cross-sectional view through the sensor of FIG. 3 on line C-C, showing an exposed electroactive surface of a working electrode surrounded by a membrane system.
- FIG. 6 is a graph depicting glucose measurements from a sensor including a silicon/hydrophilic-hydrophobic polymer blend in a diffusion resistance layer implanted in a diabetic rat model.
- FIG. 7 is a graph depicting glucose measurements from a sensor including a silicon/hydrophilic-hydrophobic polymer blend in a bioprotective layer implanted in a diabetic rat model.
- FIG. 8 is a graph depicting a sensor signal from a sensor including a silicon/hydrophilic-hydrophobic polymer blend membrane exposed to acetaminophen.
- FIG. 9 is a graph depicting a sensor signal from a sensor not including a silicon/hydrophilic-hydrophobic polymer blend membrane exposed to acetaminophen.
- analyte as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the sensing regions, devices, and methods is glucose.
- analytes are contemplated as well, including but not limited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-ß hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase
- Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids can also constitute analytes in certain embodiments.
- the analyte can be naturally present in the biological fluid or endogenous, for example, a metabolic product, a hormone, an antigen, an antibody, and the like.
- the analyte can be introduced into the body or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyot
- Analytes such as neurochemicals and other chemicals generated within the body can also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA).
- operable connection is broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to one or more components linked to another component(s) in a manner that allows transmission of signals between the components.
- one or more electrodes can be used to detect the amount of analyte in a sample and convert that information into a signal; the signal can then be transmitted to a circuit.
- the electrode is “operably linked” to the electronic circuitry.
- host as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to animals and plants, for example humans.
- electrochemically reactive surface and “electroactive surface” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the surface of an electrode where an electrochemical reaction takes place.
- a working electrode measures hydrogen peroxide produced by the enzyme catalyzed reaction of the analyte being detected reacts creating an electric current (for example, detection of glucose analyte utilizing glucose oxidase produces H 2 O 2 as a by product, H 2 O 2 reacts with the surface of the working electrode producing two protons (2H + ), two electrons (2e ⁇ ) and one molecule of oxygen (O 2 ) which produces the electronic current being detected).
- a reducible species for example, O 2 is reduced at the electrode surface in order to balance the current being generated by the working electrode.
- sensing region is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the region of a monitoring device responsible for the detection of a particular analyte.
- the sensing region generally comprises a non-conductive body, a working electrode, a reference electrode, and/or a counter electrode (optional) passing through and secured within the body forming electrochemically reactive surfaces on the body, an electronic connective means at another location on the body, and a multi-domain membrane affixed to the body and covering the electrochemically reactive surface.
- raw data stream and “data stream” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to an analog or digital signal directly related to the measured glucose concentration from the glucose sensor.
- the raw data stream is digital data in “counts” converted by an A/D converter from an analog signal (for example, voltage or amps) representative of a glucose concentration.
- the terms broadly encompass a plurality of time spaced data points from a substantially continuous glucose sensor, which comprises individual measurements taken at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes or longer.
- counts is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a unit of measurement of a digital signal.
- a raw data stream measured in counts is directly related to a voltage (for example, converted by an A/D converter), which is directly related to current from the working electrode.
- counter electrode voltage measured in counts is directly related to a voltage.
- electrical potential is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the electrical potential difference between two points in a circuit which is the cause of the flow of a current.
- Ischemia as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to local and temporary deficiency of blood supply due to obstruction of circulation to a part (for example, sensor). Ischemia can be caused by mechanical obstruction (for example, arterial narrowing or disruption) of the blood supply, for example.
- system noise is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to unwanted electronic or diffusion-related noise which can include Gaussian, motion-related, flicker, kinetic, or other white noise, for example.
- signal artifacts and “transient non-glucose related signal artifacts,” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to signal noise that is caused by substantially non-glucose reaction rate-limiting phenomena, such as ischemia, pH changes, temperature changes, pressure, and stress, for example.
- Signal artifacts, as described herein are typically transient and are characterized by higher amplitude than system noise.
- low noise as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to noise that substantially decreases signal amplitude.
- high noise and “high spikes” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to noise that substantially increases signal amplitude.
- silicon composition as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a composition of matter that comprises polymers having at least silicon and oxygen atoms in the backbone.
- distal to is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference.
- some embodiments of a device include a membrane system having a cell disruptive domain and a cell impermeable domain. If the sensor is deemed to be the point of reference and the cell disruptive domain is positioned farther from the sensor, then that domain is distal to the sensor.
- proximal to is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference.
- some embodiments of a device include a membrane system having a cell disruptive domain and a cell impermeable domain. If the sensor is deemed to be the point of reference and the cell impermeable domain is positioned nearer to the sensor, then that domain is proximal to the sensor.
- interferants and “interfering species” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and/or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement.
- interfering species can include compounds with an oxidation potential that overlaps with that of the analyte to be measured.
- Eq and Eqs (equivalents); mEq (milliequivalents); M (molar); mM (millimolar) ⁇ M (micromolar); N (Normal); mol (moles); mmol (millimoles); ⁇ mol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); ⁇ g (micrograms); Kg (kilograms); L (liters); mL (milliliters); dL (deciliters); ⁇ L (microliters); cm (centimeters); mm (millimeters); ⁇ m (micrometers); nm (nanometers); h and hr (hours); min. (minutes); s and sec. (seconds); ° C. (degrees Centigrade).
- Membrane systems of the preferred embodiments are suitable for use with implantable devices in contact with a biological fluid.
- the membrane systems can be utilized with implantable devices such as devices for monitoring and determining analyte levels in a biological fluid, for example, glucose levels for individuals having diabetes.
- the analyte-measuring device is a continuous device.
- the device can analyze a plurality of intermittent biological samples.
- the analyte-measuring device can use any method of analyte-measurement, including enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, radiometric, or the like.
- membrane systems are not limited to use in devices that measure or monitor glucose.
- These membrane systems are suitable for use in a variety of devices, including, for example, those that detect and quantify other analytes present in biological fluids (including, but not limited to, cholesterol, amino acids, alcohol, galactose, and lactate), cell transplantation devices (see, for example, U.S. Pat. Nos. 6,015,572, 5,964,745, and 6,083,523), drug delivery devices (see, for example, U.S. Pat. Nos. 5,458,631, 5,820,589, and 5,972,369), and the like.
- implantable devices that include the membrane systems of the preferred embodiments are implanted in soft tissue, for example, abdominal, subcutaneous, and peritoneal tissues, the brain, the intramedullary space, and other suitable organs or body tissues.
- the membrane systems of the preferred embodiments can be employed with a variety of known glucose measuring-devices.
- the electrode system can be used with any of a variety of known in vivo analyte sensors or monitors, such as U.S. Pat. No. 6,001,067 to Shults et al.; U.S. Pat. No. 6,702,857 to Brauker et al.; U.S. Pat. No. 6,212,416 to Ward et al.; U.S. Pat. No. 6,119,028 to Schulman et al.; U.S. Pat. No. 6,400,974 to Lesho; U.S. Pat. No.
- FIG. 1 is an exploded perspective view of one exemplary embodiment comprising an implantable glucose sensor 10 that utilizes amperometric electrochemical sensor technology to measure glucose.
- a body 12 with a sensing region 14 includes an electrode system 16 and sensor electronics, which are described in more detail with reference to FIG. 2 .
- the electrode system 16 is operably connected to the sensor electronics ( FIG. 2 ) and includes electroactive surfaces, which are covered by a membrane system 18 .
- the membrane system 18 is disposed over the electroactive surfaces of the electrode system 16 and provides one or more of the following functions: 1) supporting tissue ingrowth (cell disruptive domain); 2) protection of the exposed electrode surface from the biological environment (cell impermeable domain); 3) diffusion resistance (limitation) of the analyte (resistance domain); 4) a catalyst for enabling an enzymatic reaction (enzyme domain); 5) limitation or blocking of interfering species (interference domain); and/or 6) hydrophilicity at the electrochemically reactive surfaces of the sensor interface (electrolyte domain), for example, as described in co-pending U.S.
- the membrane system 18 of the preferred embodiments is formed at least partially from silicone materials. While not being bound by any particular theory, it is believed that silicone materials provide enhanced bio-stability when compared to other polymeric materials such as polyurethane.
- silicone cell disruptive layer (described in detail below) is used, silicone included in any underlying layer can promote bonding of the layer to the porous silicone cell disruptive layer.
- silicone has high oxygen permeability, thus promoting oxygen transport to the enzyme layer (described in detail below).
- the electrode system 16 which is located on or within the sensing region 14 , is comprised of at least a working and a reference electrode with an insulating material disposed therebetween.
- additional electrodes can be included within the electrode system, for example, a three-electrode system (working, reference, and counter electrodes) and/or including an additional working electrode (which can be used to generate oxygen, measure an additional analyte, or can be configured as a baseline subtracting electrode, for example).
- the electrode system includes three electrodes (working, counter, and reference electrodes), wherein the counter electrode is provided to balance the current generated by the species being measured at the working electrode.
- the species being measured at the working electrode is H 2 O 2 .
- Glucose oxidase, GOX catalyzes the conversion of oxygen and glucose to hydrogen peroxide and gluconate according to the following reaction:
- the change in H 2 O 2 can be monitored to determine glucose concentration because for each glucose molecule metabolized, there is a proportional change in the product H 2 O 2 .
- Oxidation of H 2 O 2 by the working electrode is balanced by reduction of ambient oxygen, enzyme generated H 2 O 2 , or other reducible species at the counter electrode.
- the H 2 O 2 produced from the glucose oxidase reaction further reacts at the surface of working electrode and produces two protons (2H+), two electrons (2e ⁇ ), and one oxygen molecule (O 2 ).
- the counter electrode utilizes oxygen as an electron acceptor, the most likely reducible species for this system are oxygen or enzyme generated peroxide. There are two main pathways by which oxygen can be consumed at the counter electrode.
- Oxygen limitations resulting in depressed function or inaccuracy as a problem of availability of oxygen to the enzyme and/or counter electrode. Oxygen limitations can also be seen during periods of transient ischemia that occur, for example, under certain postures or when the region around the implanted sensor is compressed so that blood is forced out of the capillaries. Such ischemic periods observed in implanted sensors can last for many minutes or even an hour or longer.
- FIG. 2 is a block diagram that illustrates the sensor electronics in one embodiment.
- a potentiostat 134 is shown, which is operably connected to an electrode system (such as described above) and provides a voltage to the electrodes, which biases the sensor to enable measurement of an current signal indicative of the analyte concentration in the host (also referred to as the analog portion).
- the potentiostat includes a resistor (not shown) that translates the current into voltage.
- a current to frequency converter is provided that is configured to continuously integrate the measured current, for example, using a charge counting device.
- An A/D converter 136 digitizes the analog signal into a digital signal, also referred to as “counts” for processing. Accordingly, the resulting raw data stream in counts, also referred to as raw sensor data, is directly related to the current measured by the potentiostat 134 .
- a processor module 138 includes the central control unit that controls the processing of the sensor electronics 132 .
- the processor module includes a microprocessor, however a computer system other than a microprocessor can be used to process data as described herein, for example an ASIC can be used for some or all of the sensor's central processing.
- the processor typically provides semi-permanent storage of data, for example, storing data such as sensor identifier (ID) and programming to process data streams (for example, programming for data smoothing and/or replacement of signal artifacts such as is described in U.S. Publication No. US-2005-0043598-A1).
- the processor additionally can be used for the system's cache memory, for example for temporarily storing recent sensor data.
- the processor module comprises memory storage components such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flash memory, or the like.
- the processor module comprises a digital filter, for example, an infinite impulse response (IIR) or finite impulse response (FIR) filter, configured to smooth the raw data stream from the A/D converter.
- digital filters are programmed to filter data sampled at a predetermined time interval (also referred to as a sample rate).
- time intervals also referred to as a sample rate.
- the processor module can be programmed to request a digital value from the A/D converter at a predetermined time interval, also referred to as the acquisition time.
- the values obtained by the processor are advantageously averaged over the acquisition time due the continuity of the current measurement. Accordingly, the acquisition time determines the sample rate of the digital filter.
- the processor module is configured with a programmable acquisition time, namely, the predetermined time interval for requesting the digital value from the A/D converter is programmable by a user within the digital circuitry of the processor module. An acquisition time of from about 2 seconds to about 512 seconds is preferred; however any acquisition time can be programmed into the processor module.
- a programmable acquisition time is advantageous in optimizing noise filtration, time lag, and processing/battery power.
- the processor module is configured to build the data packet for transmission to an outside source, for example, an RF transmission to a receiver as described in more detail below.
- the data packet comprises a plurality of bits that can include a preamble, a unique identifier identifying the electronics unit, the receiver, or both, (e.g., sensor ID code), data (e.g., raw data, filtered data, and/or an integrated value) and/or error detection or correction.
- the data (transmission) packet has a length of from about 8 bits to about 128 bits, preferably about 48 bits; however, larger or smaller packets can be desirable in certain embodiments.
- the processor module can be configured to transmit any combination of raw and/or filtered data.
- the transmission packet contains a fixed preamble, a unique ID of the electronics unit, a single five-minute average (e.g., integrated) sensor data value, and a cyclic redundancy code (CRC).
- CRC cyclic redundancy code
- the processor module further comprises a transmitter portion that determines the transmission interval of the sensor data to a receiver, or the like.
- the transmitter portion which determines the interval of transmission, is configured to be programmable.
- a coefficient can be chosen (e.g., a number of from about 1 to about 100, or more), wherein the coefficient is multiplied by the acquisition time (or sampling rate), such as described above, to define the transmission interval of the data packet.
- the transmission interval is programmable from about 2 seconds to about 850 minutes, more preferably from about 30 second to about 5 minutes; however, any transmission interval can be programmable or programmed into the processor module.
- a variety of alternative systems and methods for providing a programmable transmission interval can also be employed.
- data transmission can be customized to meet a variety of design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.)
- the preferred embodiments are configured to measure the current flow in the picoAmp range, and in some embodiments, femtoAmps. Namely, for every unit (mg/dL) of glucose measured, at least one picoAmp of current is measured.
- the analog portion of the A/D converter 136 is configured to continuously measure the current flowing at the working electrode and to convert the current measurement to digital values representative of the current.
- the current flow is measured by a charge counting device (e.g., a capacitor).
- a charge counting device provides a value (e.g., digital value) representative of the current flow integrated over time (e.g., integrated value).
- the value is integrated over a few seconds, a few minutes, or longer. In one exemplary embodiment, the value is integrated over 5 minutes; however, other integration periods can be chosen.
- a signal is provided, whereby a high sensitivity maximizes the signal received by a minimal amount of measured hydrogen peroxide (e.g., minimal glucose requirements without sacrificing accuracy even in low glucose ranges), reducing the sensitivity to oxygen limitations in vivo (e.g., in oxygen-dependent glucose sensors).
- the electronics unit is programmed with a specific ID, which is programmed (automatically or by the user) into a receiver to establish a secure wireless communication link between the electronics unit and the receiver.
- the transmission packet is Manchester encoded; however, a variety of known encoding techniques can also be employed.
- a battery 154 is operably connected to the sensor electronics 132 and provides the power for the sensor.
- the battery is a lithium manganese dioxide battery; however, any appropriately sized and powered battery can be used (for example, AAA, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion, zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed).
- the battery is rechargeable, and/or a plurality of batteries can be used to power the system.
- the sensor can be transcutaneously powered via an inductive coupling, for example.
- a quartz crystal 96 is operably connected to the processor 138 and maintains system time for the computer system as a whole, for example for the programmable acquisition time within the processor module.
- Optional temperature probe 140 is shown, wherein the temperature probe is located on the electronics assembly or the glucose sensor itself.
- the temperature probe can be used to measure ambient temperature in the vicinity of the glucose sensor. This temperature measurement can be used to add temperature compensation to the calculated glucose value.
- An RF module 158 is operably connected to the processor 138 and transmits the sensor data from the sensor to a receiver within a wireless transmission 160 via antenna 152 .
- a second quartz crystal 154 provides the time base for the RF carrier frequency used for data transmissions from the RF transceiver.
- other mechanisms such as optical, infrared radiation (IR), ultrasonic, or the like, can be used to transmit and/or receive data.
- the hardware and software are designed for low power requirements to increase the longevity of the device (for example, to enable a life of from about 3 to about 24 months, or more) with maximum RF transmittance from the in vivo environment to the ex vivo environment for wholly implantable sensors (for example, a distance of from about one to ten meters or more).
- a high frequency carrier signal of from about 402 MHz to about 433 MHz is employed in order to maintain lower power requirements.
- the RF module employs a one-way RF communication link to provide a simplified ultra low power data transmission and receiving scheme.
- the RF transmission can be OOK or FSK modulated, preferably with a radiated transmission power (EIRP) fixed at a single power level of typically less than about 100 microwatts, preferably less than about 75 microwatts, more preferably less than about 50 microwatts, and most preferably less than about 25 microwatts.
- EIRP radiated transmission power
- the carrier frequency may be adapted for physiological attenuation levels, which is accomplished by tuning the RF module in a simulated in vivo environment to ensure RF functionality after implantation; accordingly, the preferred glucose sensor can sustain sensor function for 3 months, 6 months, 12 months, or 24 months or more.
- sensor electronics associated with the electronics unit is applicable to a variety of continuous analyte sensors, such as non-invasive, minimally invasive, and/or invasive (e.g., transcutaneous and wholly implantable) sensors.
- sensor electronics and data processing as well as the receiver electronics and data processing described below can be incorporated into the wholly implantable glucose sensor disclosed in U.S. Publication No. US-2005-0245799-A1 and U.S. patent application Ser. No. 10/885,476 filed Jul. 6, 2004 and entitled, “SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM.”
- a transcutaneous wire sensor is utilized.
- This sensor comprises a platinum wire working electrode 144 with insulating coating 145 (e.g., parylene).
- a silver or silver/silver chloride reference electrode wire 146 is helically wound around the insulating coating 145 .
- a portion of the insulating coating 145 is removed to create an exposed electroactive window 143 around which a membrane as described herein can be disposed. Further details regarding such wire sensors may be found in U.S application Ser. No. 11/157,746, filed Jun. 21, 2005 and entitled “TRANSCUTANEOUS ANALYTE SENSOR,” which is incorporated herein by reference in its entirety.
- the membrane system 18 can include two or more layers that cover an implantable device, for example, an implantable glucose sensor.
- two or more layers of the membrane system may be disposed on a transcutaneous wire sensor.
- the membrane prevents direct contact of the biological fluid sample with the electrodes, while controlling the permeability of selected substances (for example, oxygen and glucose) present in the biological fluid through the membrane for reaction in an enzyme rich domain with subsequent electrochemical reaction of formed products at the electrodes.
- the membrane systems of preferred embodiments are constructed of one or more membrane layers. Each distinct layer can comprise the same or different materials. Furthermore, each layer can be homogenous or alternatively may comprise different domains or gradients where the composition varies.
- FIG. 4 is an illustration of a membrane system in one preferred embodiment.
- the membrane system 18 can be used with a glucose sensor such, as is described above with reference to FIG. 1 .
- the membrane system 18 includes a cell disruptive layer 40 most distal of all domains from the electrochemically reactive surfaces, a bioprotective layer 42 less distal from the electrochemically reactive surfaces than the cell disruptive layer, a diffusion resistance layer 44 less distal from the electrochemically reactive surfaces than the bioprotective layer, an enzyme layer 46 less distal from the electrochemically reactive surfaces than the diffusion resistance layer, an interference layer 48 less distal from the electrochemically reactive surfaces than the enzyme layer, and an electrode layer 50 adjacent to the electrochemically reactive surfaces.
- the membrane system can be modified for use in other devices, by including only two or more of the layers, or additional layers not recited above.
- FIG. 5 is an illustration of a membrane system in one preferred embodiment of a transcutaneous wire sensor.
- FIG. 5 is a cross-sectional view through the sensor of FIG. 3 on line C-C.
- the membrane system includes an electrode layer 147 , an interference layer 148 , and enzyme layer 149 , and a diffusion resistance layer 150 wrapped around the platinum wire working electrode 144 .
- this membrane system also includes a cell impermeable layer as described below.
- the transcutaneous wire sensor is configured for short-term implantation (e.g., 1-30 days). Accordingly, in these embodiments, the cell disruptive layer may not be required because a foreign body capsule does not form in the short duration of implantation.
- the membrane systems for use in implantable sensors is formed as a physically continuous membrane, namely, a membrane having substantially uniform physical structural characteristics from one side of the membrane to the other.
- the membrane can have chemically heterogeneous domains, for example, domains resulting from the use of block copolymers (for example, polymers in which different blocks of identical monomer units alternate with each other), but can be defined as homogeneous overall in that each of the above-described layers functions by the preferential diffusion of some substance through the homogeneous membrane.
- Some layers of the membrane systems 18 of the preferred embodiments include materials with high oxygen solubility.
- the membrane systems 18 with high oxygen solubility simultaneously permit efficient transport of aqueous solutions of the analyte.
- one or more layer(s) is/are formed from a composition that, in addition to providing high oxygen solubility, allows for the transport of glucose or other such water-soluble molecules (for example, drugs).
- these layers comprise a blend of a silicone polymer with a hydrophilic polymer.
- hydrophilic polymer it is meant that the polymer has a substantially hydrophilic domain in which aqueous substances can easily dissolve.
- the hydrophilic polymer has a molecular weight of at least about 1000 g/mol, 5,000 g/mol, 8,000 g/mol, 10,000 g/mol, or 15,000 g/mol.
- the hydrophilic polymer comprises both a hydrophilic domain and a partially hydrophobic domain (e.g., a copolymer).
- the hydrophobic domain(s) facilitate the blending of the hydrophilic polymer with the hydrophobic silicone polymer.
- the hydrophobic domain is itself a polymer (i.e., a polymeric hydrophobic domain).
- the hydrophobic domain is not a simple molecular head group but is rather polymeric.
- the molecular weight of any covalently continuous hydrophobic domain within the hydrophilic polymer is at least about 500 g/mol, 700 g/mol, 1000 g/mol, 2000 g/mol, 5000 g/mol, or 8,000 g/mol. In various embodiments, the molecular weight of any covalently continuous hydrophilic domain within the hydrophilic polymer is at least about 500 g/mol, 700 g/mol, 1000 g/mol, 2000 g/mol, 5000 g/mol, or 8,000 g/mol.
- the ratio of the silicone polymer to hydrophilic polymer in a particular layer is selected to provide an amount of oxygen and water-soluble molecule solubility such that oxygen and water-soluble molecule transport through the layer is optimized according to the desired function of that particular layer. Furthermore, in some embodiments, the ratio of silicone polymer to hydrophilic polymer as well as the polymeric compositions are selected such that a layer constructed from the material has interference characteristics that inhibit transport of one or more interfering species through the layer.
- Some known interfering species for a glucose sensor include, but are not limited to, acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid. Accordingly, in some embodiments, a silicone polymer/hydrophilic polymer layer as disclosed herein is less permeable to one or more of these interfering species than to the analyte, e.g., glucose.
- silicone polymer/hydrophilic polymer blends are used in multiple layers of a membrane.
- the ratio of silicone polymer to hydrophilic polymer in the layers incorporating the blends varies according to the desired functionality of each layer.
- the relative amounts of silicone polymer and hydrophilic polymer described below are based on the respective amounts found in the cured polymeric blend. Upon introduction into an aqueous environment, some of the polymeric components may leach out, thereby changing the relative amounts of silicone polymer and hydrophilic polymer. For example, significant amounts of the portions of the hydrophilic polymer that are not cross-linked may leach out.
- the amount of any cross-linking between the silicone polymer and the hydrophilic polymer is substantially limited. In various embodiments, at least about 75%, 85%, 95%, or 99% of the silicone polymer is not covalently linked to the hydrophilic polymer. In some embodiments, the silicone polymer and the hydrophilic polymer do not cross link at all unless a cross-linking agent is used (e.g., such as described below). Similarly, in some embodiments, the amount of any entanglement (e.g., blending on a molecular level) between the silicone polymer and the hydrophilic polymer is substantially limited. In one embodiment, the silicone polymer and hydrophilic polymers form microdomains. For example, in one embodiment, the silicone polymer forms micellar structures surrounded by a network of hydrophilic polymer.
- the silicone polymer for use in the silicone/hydrophilic polymer blend may be any suitable silicone polymer.
- the silicone polymer is a liquid silicone rubber that may be vulcanized using a metal- (e.g., platinum), peroxide-, heat-, ultraviolet-, or other radiation-catalyzed process.
- the silicone polymer is a dimethyl- and methylhydrogen-siloxane copolymer.
- the copolymer has vinyl substituents.
- commercially available silicone polymers may be used.
- commercially available silicone polymer precursor compositions may be used to prepare the blends, such as described below.
- MED-4840 available from NUSIL® Technology LLC is used as a precursor to the silicone polymer used in the blend.
- MED-4840 consists of a 2-part silicone elastomer precursor including vinyl-functionalized dimethyl- and methylhydrogen-siloxane copolymers, amorphous silica, a platinum catalyst, a crosslinker, and an inhibitor. The two components may be mixed together and heated to initiate vulcanization, thereby forming an elastomeric solid material.
- Suitable silicone polymer precursor systems include, but are not limited to, MED-2174 peroxide-cured liquid silicone rubber available from NUSIL® Technology LLC, SILASTIC® MDX4-4210 platinum-cured biomedical grade elastomer available from DOW CORNING®, and Implant Grade Liquid Silicone Polymer (durometers 10-50) available from Applied Silicone Corporation.
- the hydrophilic polymer for use in the blend may be any suitable hydrophilic polymer, including but not limited to components such as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate, polyvinylalcohol, polyacrylic acid, polyethers such as polyethylene glycol or polypropylene oxide, and copolymers thereof, including, for example, di-block, tri-block, alternating, random, comb, star, dendritic, and graft copolymers (block copolymers are discussed in U.S. Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein by reference).
- PVP polyvinylpyrrolidone
- PVP polyhydroxyethyl methacrylate
- polyvinylalcohol polyacrylic acid
- polyethers such as polyethylene glycol or polypropylene oxide
- copolymers thereof including, for example, di-block, tri-block, alternating, random, comb, star, dendritic,
- the hydrophilic polymer is a copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). Suitable such polymers include, but are not limited to, PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating block copolymers of PEO-PPO, random copolymers of ethylene oxide and propylene oxide, and blends thereof. In some embodiments, the copolymers may be optionally substituted with hydroxy substituents. Commercially available examples of PEO and PPO copolymers include the PLURONIC® brand of polymers available from BASF®. Some PLURONIC® polymers are triblock copolymers of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) having the general molecular structure:
- the repeat units x and y vary among various PLURONIC® products.
- the poly(ethylene oxide) blocks act as a hydrophilic domain allowing the dissolution of aqueous agents in the polymer.
- the poly(propylene oxide) block acts as a hydrophobic domain facilitating the blending of the PLURONIC® polymer with a silicone polymer.
- PLURONIC® F-127 is used having x of approximately 100 and y of approximately 65.
- the molecular weight of PLURONIC® F-127 is approximately 12,600 g/mol as reported by the manufacture.
- Other PLURONIC® polymers include PPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products).
- Other suitable commercial polymers include, but are not limited to, SYNPERONICS® products available from UNIQEMA®.
- the polyether structure of PLURONIC® polymers is relatively inert. Accordingly, without being bound by any particular theory, it is believed that the PLURONIC® polymers do not substantially react with the components in MED-4840 or other silicone polymer precursors.
- copolymers having hydrophilic and hydrophobic domains may be used.
- a triblock copolymer having the structure hydrophobic-hydrophilic-hydrophobic may be used.
- a diblock copolymer having the structure hydrophilic-hydrophobic is used.
- Layers that include a silicone polymer-hydrophilic polymer blend may be made using any of the methods of forming polymer blends known in the art.
- a silicone polymer precursor e.g., MED-4840
- a hydrophilic polymer e.g., PLURONIC® F-127 dissolved in a suitable solvent such as acetone, ethyl alcohol, or 2-butanone.
- the mixture may then be drawn into a film or applied in a multi-layer membrane structure using any method known in the art (e.g., spraying, painting, dip coating, vapor depositing, molding, 3-D printing, lithographic techniques (e.g., photolithograph), micro- and nano-pipetting printing techniques, etc.).
- the mixture may then be cured under high temperature (e.g., 50-150° C.).
- high temperature e.g., 50-150° C.
- Other suitable curing methods include ultraviolet or gamma radiation, for example.
- the silicone polymer precursor will vulcanize and the solvent will evaporate.
- the preformed layer is the cell disruptive layer.
- the cell disruptive layer comprises a preformed porous silicone membrane.
- the cell disruptive layer is also formed from a silicone polymer/hydrophilic polymer blend.
- multiple films are applied on top of the preformed layer. Each film may posses a finite interface with adjacent films or may together form a physically continuous structure having a gradient in chemical composition.
- cross-linking agent may also be included in the mixture to induce cross-linking between hydrophilic polymer molecules.
- a cross-linking system that reacts with pendant or terminal hydroxy groups or methylene, ethylene, or propylene hydrogen atoms may be used to induce cross linking.
- suitable cross-linking agents include ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP).
- these cross-linking agents are believed to react primarily with the PLURONIC® polymer with some amount possibly inducing cross-linking in the silicone polymer or between the PLURONIC® polymer and the silicone polymer.
- enough cross-linking agent is added such that the ratio of cross-linking agent molecules to hydrophilic polymer molecules added when synthesizing the blend is about 10 to about 30 (e.g., about 15 to about 20).
- from about 0.5% to about 15% w/w of cross-linking agent is added relative to the total dry weights of cross-linking agent, silicone polymer, and hydrophilic polymer added when blending the ingredients (in one example, about 1% to about 10%).
- from about 5% to about 30% of the dry ingredient weight is the PLURONIC® polymer.
- substantially all of the cross-linking agent is believed to react, leaving substantially no detectable unreacted cross-linking agent in the final film.
- BHT butylhydroxy toluene
- PLURONIC® PLURONIC
- precursors of both the silicone polymer and hydrophilic polymer may be mixed prior to curing such that polymerization of both the silicone polymer and the hydrophilic polymer occur during curing.
- already polymerized silicone polymer is mixed with a hydrophilic polymer such that no significant polymerization occurs during curing.
- the cell disruptive layer 40 is positioned most distal to the implantable device and is designed to support tissue ingrowth, to disrupt contractile forces typically found in a foreign body capsule, to encourage vascularity within the membrane, and/or to disrupt the formation of a barrier cell layer.
- the cell disruptive layer 40 has an open-celled configuration with interconnected cavities and solid portions, wherein the distribution of the solid portion and cavities of the cell disruptive layer includes a substantially co-continuous solid domain and includes more than one cavity in three dimensions substantially throughout the entirety of the first domain. Cells can enter into the cavities; however they cannot travel through or wholly exist within the solid portions. The cavities allow most substances to pass through, including, for example, cells, and molecules.
- the cell disruptive layer 40 is preferably formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like. In these embodiments, transport of water-soluble agents such as an aqueous analyte occurs primarily through the pores and cavities of the layer.
- the cell disruptive domain is formed from polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polytetrafluoroethylene, polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polysulfones or block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers.
- PP polypropylene
- PVC polyvinylchloride
- PVDF polyvinylidene fluoride
- PBT polybutylene terephthalate
- PMMA polymethylmethacrylate
- the cell disruptive layer is formed from a silicone composition with a non-silicon containing hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, or carbonates covalently incorporated or grafted therein such that water-soluble agents can also be transported through polymeric matrix of the cell disruptive layer 40 .
- a silicone composition with a non-silicon containing hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, or carbonates covalently incorporated or grafted therein such that water-soluble agents can also be transported through polymeric matrix of the cell disruptive layer 40 .
- a non-silicon containing hydrophile such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, or carbonates covalently incorporated or grafted therein such that water-soluble agents can also be transported through polymeric matrix of the cell disruptive layer 40 .
- the cell disruptive layer is formed from a monomer, polymer, copolymer, or blend including one or more of: lactic acid, glycolic acid, anhydrides, phospazenes, vinyl alcohol, ethylene vinyl alcohol, acetates, ⁇ -caprolactone, ⁇ -hydroxybutyrate, ⁇ -ethyl glutamate, DTH iminocarbonate, Bisphenol A iminocarbonate, sebacic acid, hexadecanoic acid, saccharides, chitosan, hydyoxyethyl methacrylate (HEMA), ceramics, hyaluronic acid (HA), collagen, gelatin, starches, hydroxy apatite, calcium phosphates, bioglasses, amino acid sequences, proteins, glycoproteins, protein fragments, agarose, fibrin, n-butylene, isobutylene, dioxanone, nylons, vinyl chlorides, amides, ethylenes, n-butyl
- the cell disruptive layer 40 is formed from silicone polymer/hydrophilic polymer blends such as described above. Due to the open-cell configuration of the cell disruptive layer 40 , the ratio of silicone polymer to hydrophilic polymer may be chosen to increase the structural integrity of the layer so that the open-cell configuration is maintained. Alternatively, the structural integrity of the cell disruptive layer can be increased by choosing a silicone polymer having properties suitable for increasing structural integrity (e.g., a silicone polymer having an increased durometer). In one embodiment, the concentration of hydrophilic polymer (e.g., PLURONIC® F-127) relative to silicone polymer (e.g., MED-4840) is from about 1% to about 30%, preferably from about 5% to about 20% in the cell disruptive layer 40 .
- silicone polymer/hydrophilic polymer blends such as described above. Due to the open-cell configuration of the cell disruptive layer 40 , the ratio of silicone polymer to hydrophilic polymer may be chosen to increase the structural integrity of the layer so that the open-cell configuration is maintained. Alternatively,
- the thickness of the cell disruptive domain is from about 10 or less, 20, 30, 40, 50, 60, 70, 80, or 90 microns to about 1500, 2000, 2500, or 3000 or more microns. In more preferred embodiments, the thickness of the cell disruptive domain is from about 100, 150, 200 or 250 microns to about 1000, 1100, 1200, 1300, or 1400 microns. In even more preferred embodiments, the thickness of the cell disruptive domain is from about 300, 350, 400, 450, 500, or 550 microns to about 500, 550, 600, 650, 700, 750, 800, 850, or 900 microns.
- the cell disruptive domain is optional and can be omitted when using an implantable device that does not prefer tissue ingrowth, for example, a short-lived device (for example, less than one day to about a week or up to about one month) or one that delivers tissue response modifiers.
- a short-lived device for example, less than one day to about a week or up to about one month
- the bioprotective layer 42 is positioned less distal to the implantable device than the cell disruptive layer, and can be resistant to cellular attachment, impermeable to cells, and/or is composed of a biostable material.
- the bioprotective layer is resistant to cellular attachment (for example, attachment by inflammatory cells, such as macrophages, which are therefore kept a sufficient distance from other domains, for example, the enzyme domain), hypochlorite and other oxidizing species are short-lived chemical species in vivo, and biodegradation does not occur.
- the materials preferred for forming the bioprotective layer 42 may be resistant to the effects of these oxidative species and have thus been termed biodurable. See, for example, U.S. Pat. No. 6,702,857, filed Jul.
- bioprotective layer 42 is formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like.
- the cell impermeable domain is formed from a silicone composition with a hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, carbonates, or polypropylene glycol covalently incorporated or grafted therein.
- the bioprotective layer is formed from a monomer, polymer, copolymer, or blend including one or more of: lactic acid, glycolic acid, anhydrides, phospazenes, vinyl alcohol, ethylene vinyl alcohol, acetates, ⁇ -caprolactone, ⁇ -hydroxybutyrate, ⁇ -ethyl glutamate, DTH iminocarbonate, Bisphenol A iminocarbonate, sebacic acid, hexadecanoic acid, saccharides, chitosan, hydyoxyethyl methacrylate (HEMA), ceramics, hyaluronic acid (HA), collagen, gelatin, starches, hydroxy apatite, calcium phosphates, bioglasses, amino acid sequences, proteins, glycoproteins, protein fragments, agarose, fibrin, n-butylene, isobutylene, dioxanone, nylons, vinyl chlorides, amides, ethylenes, n-butylene,
- the bioprotective layer 42 is formed from silicone polymer/hydrophilic polymer blends such as described above. It is advantageous that the cell impermeable layer 42 have both high oxygen and aqueous analyte solubility so that sufficient reactants reach the enzyme layer. Accordingly, in one embodiment, the concentration of hydrophilic polymer (e.g., PLURONIC® F-127) relative to silicone polymer (e.g., MED-4840) is relatively high, e.g., from about 10% to about 30% in the bioprotective layer 42 . In one embodiment, the concentration of hydrophilic polymer is from about 15% to about 25% (e.g., about 20%).
- silicone polymer e.g., MED-4840
- the thickness of the bioprotective layer is from about 10 or 15 microns or less to about 125, 150, 175, 200 or 250 microns or more. In more preferred embodiments, the thickness of the bioprotective layer is from about 20, 25, 30, or 35 microns to about 60, 65, 70, 75, 80, 85, 90, 95, or 100 microns. In even more preferred embodiments, the bioprotective layer is from about 20 or 25 microns to about 50, 55, or 60 microns thick.
- the cell disruptive layer 40 and bioprotective layer 42 of the membrane system can be formed together as one unitary structure.
- the cell disruptive and bioprotective layers 40 , 42 of the membrane system can be formed as two layers mechanically or chemically bonded together.
- the cell disruptive layer 40 and bioprotective layer 42 consist of a unitary structure having graduated properties.
- the porosity of the unitary structure may vary from high porosity at the tissue side of the layer to very low or no porosity at the sensor side.
- the chemical properties of such a graduated structure may also vary.
- the concentration of the hydrophilic polymer may vary throughout the structure, increasing in concentration toward the sensor side of the layer. The lower concentration on the tissue side allows for increased structural integrity to support an open-celled structure while the higher concentration on the sensor side promotes increased transport of aqueous analytes through the polymer blend.
- the diffusion resistance layer 44 or 150 is situated more proximal to the implantable device relative to the cell disruptive layer.
- the diffusion resistance layer controls the flux of oxygen and other analytes (for example, glucose) to the underlying enzyme domain.
- oxygen and other analytes for example, glucose
- an immobilized enzyme-based sensor employing oxygen as cofactor is supplied with oxygen in non-rate-limiting excess in order to respond linearly to changes in glucose concentration, while not responding to changes in oxygen tension.
- a linear response to glucose levels can be obtained only up to about 40 mg/dL.
- a linear response to glucose levels is desirable up to at least about 500 mg/dL.
- the diffusion resistance layer 44 or 150 includes a semipermeable membrane that controls the flux of oxygen and glucose to the underlying enzyme layer 46 or 147 , preferably rendering oxygen in non-rate-limiting excess. As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which is achieved without the diffusion resistance layer. In one embodiment, the diffusion resistance layer 44 or 150 exhibits an oxygen-to-glucose permeability ratio of approximately 200:1. As a result, one-dimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529 (1994)).
- a lower ratio of oxygen-to-glucose can be sufficient to provide excess oxygen by using a high oxygen soluble domain (for example, a silicone material) to enhance the supply/transport of oxygen to the enzyme membrane and/or electroactive surfaces.
- a high oxygen soluble domain for example, a silicone material
- glucose concentration can be less of a limiting factor. In other words, if more oxygen is supplied to the enzyme and/or electroactive surfaces, then more glucose can also be supplied to the enzyme without creating an oxygen rate-limiting excess.
- the diffusion resistance layer 44 or 150 is preferably formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like.
- the resistance domain is formed from a silicone composition with a hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, carbonates, or polypropylene glycol covalently incorporated or grafted therein.
- the diffusion resistance layer is formed from polyurethane, for example, a polyurethane urea/polyurethane-block-polyethylene glycol blend.
- the diffusion resistance layer is formed from a monomer, polymer, copolymer, or blend including one or more of: lactic acid, glycolic acid, anhydrides, phospazenes, vinyl alcohol, ethylene vinyl alcohol, acetates, ⁇ -caprolactone, ⁇ -hydroxybutyrate, ⁇ -ethyl glutamate, DTH iminocarbonate, Bisphenol A iminocarbonate, sebacic acid, hexadecanoic acid, saccharides, chitosan, hydyoxyethyl methacrylate (HEMA), ceramics, hyaluronic acid (HA), collagen, gelatin, starches, hydroxy apatite, calcium phosphates, bioglasses, amino acid sequences, proteins, glycoproteins, protein fragments, agarose, fibrin, n-butylene, isobutylene, dioxanone, nylons, vinyl chlorides, amides, ethylenes, n-butyl
- the diffusion resistance layer 44 or 150 is formed from silicone polymer/hydrophilic polymer blends such as described above. In some alternative embodiments, the diffusion resistance layer 44 or 150 is formed from silicone polymer/hydrophilic polymer blends.
- the concentration of hydrophilic polymer e.g., PLURONIC® F-127 relative to silicone polymer (e.g., MED-4840) is from about 1% to about 15% in the diffusion resistance layer 44 (e.g., from about 6% to about 10%).
- the diffusion resistance layer includes a polyurethane membrane with both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to an analyte sensor, the membrane being fabricated easily and reproducibly from commercially available materials.
- a suitable hydrophobic polymer component is a polyurethane, or polyetherurethaneurea.
- Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material.
- a polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material.
- Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units.
- Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the membranes of preferred embodiments.
- the material that forms the basis of the hydrophobic matrix of the diffusion resistance layer can be any of those known in the art as appropriate for use as membranes in sensor devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow an oxygen molecule to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes.
- non-polyurethane type membranes examples include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein based materials, and mixtures or combinations thereof.
- the hydrophilic polymer component is polyethylene oxide.
- one useful hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide.
- the polyethylene oxide portions of the copolymer are thermodynamically driven to separate from the hydrophobic portions of the copolymer and the hydrophobic polymer component.
- the 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.
- the diffusion resistance layer 44 or 150 can be formed as a unitary structure with the bioprotective layer 42 ; that is, the inherent properties of the diffusion resistance layer 44 or 150 can provide the functionality described with reference to the bioprotective layer 42 such that the bioprotective layer 42 is incorporated as a part of diffusion resistance layer 44 or 150 .
- the combined diffusion resistance layer/bioprotective layer can be bonded to or formed as a skin on the cell disruptive layer 40 .
- the diffusion resistance layer/bioprotective layer may also be part of a unitary structure with the cell disruptive layer 40 such that the outer layer of the membrane system is graduated to the interface with the enzyme layer.
- the diffusion resistance layer/bioprotective layer may also be part of a unitary structure with the cell disruptive layer 40 including a chemical gradient with transition properties between the outer layer and the enzyme layer.
- the diffusion resistance layer 44 or 150 is formed as a distinct layer and chemically or mechanically bonded to the cell disruptive layer 40 (if applicable) or the bioprotective layer 42 (when the resistance domain is distinct from the cell impermeable domain).
- the diffusion resistance layer may be a distinct layer from the cell disruptive layer or the bioprotective layer but may nonetheless include a chemical gradient such that its diffusion resistance property transitions from one side of the layer to the other.
- the cell disruptive layer and bioprotective layers may also include a chemical gradient. Where multiple such layers have chemical gradients, the chemical compositions at the interface between two layers may be identical or different.
- the thickness of the resistance domain is from about 0.05 microns or less to about 200 microns or more. In more preferred embodiments, the thickness of the resistance domain is from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 10, 15, 20, 25, 30, or 35 microns to about, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, or 100 microns.
- the thickness of the resistance domain is from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case of a transcutaneously implanted sensor or from about 20 or 25 microns to about 40 or 50 microns in the case of a wholly implanted sensor.
- an immobilized enzyme layer 46 or 149 is situated less distal from the electrochemically reactive surfaces than the diffusion resistance layer 44 or 150 .
- the immobilized enzyme layer 46 or 149 comprises glucose oxidase.
- the immobilized enzyme layer 46 or 149 can be impregnated with other oxidases, for example, galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, or uricase.
- oxidases for example, galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, or uricase.
- the sensor's response should neither be limited by enzyme activity nor cofactor concentration.
- the enzyme layer 44 or 149 is preferably formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like.
- the enzyme domain is formed from a silicone composition with a hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, carbonates, or polypropylene glycol covalently incorporated or grafted therein.
- the enzyme layer 44 or 149 is formed from polyurethane.
- high oxygen solubility within the enzyme layer can be achieved by using a polymer matrix to host the enzyme within the enzyme layer that has a high solubility of oxygen.
- the solubility of oxygen within a perfluorocarbon-based polymer is 50-volume %.
- the solubility of oxygen in water is approximately 2-volume %.
- the enzyme layer is formed from silicone polymer/hydrophilic polymer blends such as described above.
- the concentration of hydrophilic polymer e.g., PLURONIC® F-127 relative to silicone polymer (e.g., MED-4840) is relatively high, e.g., from about 10% to about 30% in the bioprotective layer 42 .
- the concentration of hydrophilic polymer is from about 15% to about 25% (e.g., about 20%).
- Utilization of a high oxygen solubility material for the enzyme layer is advantageous because the oxygen dissolves more readily within the layer and thereby acts as a high oxygen soluble domain optimizing oxygen availability to oxygen-utilizing sources (for example, the enzyme and/or counter electrode).
- oxygen-utilizing sources for example, the enzyme and/or counter electrode.
- the diffusion resistance layer 44 or 149 and enzyme layer 46 or 150 both comprise a high oxygen soluble material, the chemical bond between the enzyme layer 46 or 150 and diffusion resistance layer 44 or 149 can be optimized, and the manufacturing made easy.
- the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme.
- the thickness of the enzyme domain is from about 0.05 micron or less to about 20, 30 40, 50, 60, 70, 80, 90, or 100 microns or more. In more preferred embodiments, the thickness of the enzyme domain is between about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 microns and 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 25, or 30 microns.
- the thickness of the enzyme domain is from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case of a transcutaneously implanted sensor or from about 6, 7, or 8 microns to about 9, 10, 11, or 12 microns in the case of a wholly implanted sensor.
- the interference layer 48 or 148 is situated less distal to the implantable device than the immobilized enzyme layer.
- Interferants are molecules or other species that are electro-reduced or electro-oxidized at the electrochemically reactive surfaces, either directly or via an electron transfer agent, to produce a false signal (for example, urate, ascorbate, or acetaminophen).
- the interference layer 48 or 148 prevents the penetration of one or more interferants into the electrolyte phase around the electrochemically reactive surfaces.
- this type of interference layer is much less permeable to one or more of the interferants than to the analyte.
- the interference domain 48 or 148 can include ionic components incorporated into a polymeric matrix to reduce the permeability of the interference layer to ionic interferants having the same charge as the ionic components.
- the interference layer 48 or 148 includes a catalyst (for example, peroxidase) for catalyzing a reaction that removes interferants.
- a catalyst for example, peroxidase
- the interference layer 48 or 148 includes a thin membrane that is designed to limit diffusion of species, for example, those greater than 34 kD in molecular weight, for example.
- the interference layer permits analytes and other substances (for example, hydrogen peroxide) that are to be measured by the electrodes to pass through, while preventing passage of other substances, such as potentially interfering substances.
- the interference layer 48 or 148 is constructed of polyurethane.
- the interference layer 48 or 148 comprises a high oxygen soluble polymer.
- the interference layer 48 or 148 is formed from silicone polymer/hydrophilic polymer blends such as described above. As described herein, such polymer blends can have the characteristics of limiting transport of one or more interferants therethrough. Because of this property, the use of the polymer blends in a membrane layer other than the interference layer may also confer interferant resistance properties in those layers, potentially eliminating the need for a separate interference layer. In some embodiments, these layers allow diffusion of glucose therethrough but limit diffusion of one or more interferant therethrough.
- the interference layer 48 or 148 is formed from one or more cellulosic derivatives.
- cellulosic derivatives include polymers such as cellulose acetate, cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, and the like.
- the interference layer 48 or 148 is formed from cellulose acetate butyrate.
- a casting solution or dispersion of cellulose acetate butyrate at a weight percent of about 15% to about 25%, preferably from about 15%, 16%, 17%, 18%, 19% to about 20%, 21%, 22%, 23%, 24% or 25%, and more preferably about 18% is preferred.
- the casting solution includes a solvent or solvent system, for example an acetone:ethanol solvent system. Higher or lower concentrations can be preferred in certain embodiments.
- a plurality of layers of cellulose acetate butyrate can be advantageously combined to form the interference domain in some embodiments, for example, three layers can be employed.
- cellulose acetate butyrate components with different molecular weights in a single solution, or to deposit multiple layers of cellulose acetate butyrate from different solutions comprising cellulose acetate butyrate of different molecular weights, different concentrations, and/or different chemistries (e.g., functional groups). It can also be desirable to include additional substances in the casting solutions or dispersions, e.g., functionalizing agents, crosslinking agents, other polymeric substances, substances capable of modifying the hydrophilicity/hydrophobicity of the resulting layer, and the like.
- additional substances in the casting solutions or dispersions e.g., functionalizing agents, crosslinking agents, other polymeric substances, substances capable of modifying the hydrophilicity/hydrophobicity of the resulting layer, and the like.
- the interference layer 48 or 148 is formed from cellulose acetate.
- Cellulose acetate with a molecular weight of about 30,000 daltons or less to about 100,000 daltons or more, preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000 daltons, and more preferably about 50,000 daltons is preferred.
- a casting solution or dispersion of cellulose acetate at a weight percent of about 3% to about 10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5% to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about 8% is preferred.
- higher or lower molecular weights and/or cellulose acetate weight percentages can be preferred. It can be desirable to employ a mixture of cellulose acetates with molecular weights in a single solution, or to deposit multiple layers of cellulose acetate from different solutions comprising cellulose acetates of different molecular weights, different concentrations, or different chemistries (e.g., functional groups). It can also be desirable to include additional substances in the casting solutions or dispersions such as described in more detail above.
- Layer(s) prepared from combinations of cellulose acetate and cellulose acetate butyrate, or combinations of layer(s) of cellulose acetate and layer(s) of cellulose acetate butyrate can also be employed to form the interference layer 48 or 148 .
- additional polymers such as Nafion®
- cellulosic derivatives can be used in combination with cellulosic derivatives to provide equivalent and/or enhanced function of the interference layer 48 or 148 .
- a 5 wt % Nafion® casting solution or dispersion can be used in combination with a 8 wt % cellulose acetate casting solution or dispersion, e.g., by dip coating at least one layer of cellulose acetate and subsequently dip coating at least one layer Nafion® onto a needle-type sensor such as described with reference to the preferred embodiments. Any number of coatings or layers formed in any order may be suitable for forming the interference domain of the preferred embodiments.
- more than one cellulosic derivative can be used to form the interference layer 48 or 148 of the preferred embodiments.
- the formation of the interference domain on a surface utilizes a solvent or solvent system in order to solvate the cellulosic derivative (or other polymer) prior to film formation thereon.
- acetone and ethanol are used as solvents for cellulose acetate; however one skilled in the art appreciates the numerous solvents that are suitable for use with cellulosic derivatives (and other polymers).
- the preferred relative amounts of solvent can be dependent upon the cellulosic derivative (or other polymer) used, its molecular weight, its method of deposition, its desired thickness, and the like.
- a percent solute of from about 1% to about 25% is preferably used to form the interference domain solution so as to yield an interference layer 48 or 148 having the desired properties.
- the cellulosic derivative (or other polymer) used, its molecular weight, method of deposition, and desired thickness can be adjusted, depending upon one or more other of the parameters, and can be varied accordingly as is appreciated by one skilled in the art.
- interference layer 48 or 148 other polymer types that can be utilized as a base material for the interference layer 48 or 148 include polyurethanes, polymers having pendant ionic groups, and polymers having controlled pore size, for example.
- the interference domain includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species.
- the interference layer 48 or 148 is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid.
- Other systems and methods for reducing or eliminating interference species that can be applied to the membrane system of the preferred embodiments are described in co-pending U.S. patent application Ser. No. 10/896,312 filed Jul.
- the thickness of the interference domain is from about 0.05 microns or less to about 20 microns or more. In more preferred embodiments, the thickness of the interference domain is between about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns and about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns. In more preferred embodiments, the thickness of the interference domain is from about 0.6, 0.7, 0.8, 0.9, or 1 micron to about 2, 3, or 4 microns.
- An electrode layer 50 or 147 is situated more proximal to the electrochemically reactive surfaces than the interference layer 48 or 148 .
- the electrode layer 50 or 147 includes a semipermeable coating that maintains hydrophilicity at the electrochemically reactive surfaces of the sensor interface.
- the electrode layer 50 or 147 enhances the stability of the interference layer 48 or 148 by protecting and supporting the material that makes up the interference layer.
- the electrode layer 50 or 147 also assists in stabilizing the operation of the device by overcoming electrode start-up problems and drifting problems caused by inadequate electrolyte.
- the buffered electrolyte solution contained in the electrode layer also protects against pH-mediated damage that can result from the formation of a large pH gradient between the substantially hydrophobic interference domain and the electrodes due to the electrochemical activity of the electrodes.
- the electrode layer may not be used, for example, when an interference layer is not provided.
- the electrode layer 50 or 147 includes a flexible, water-swellable, substantially solid gel-like film (e.g., a hydrogel) having a “dry film” thickness of from about 0.05 microns to about 100 microns, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5, 4, 4.5, 5, or 5.5 to about 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 30, 40, 50, 60, 70, 80, 90, or 100 microns.
- a flexible, water-swellable, substantially solid gel-like film e.g., a hydrogel having a “dry film” thickness of from about 0.05 microns to about 100 microns, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,
- the thickness of the electrolyte domain is from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case of a transcutaneously implanted sensor or from about 6, 7, or 8 microns to about 9, 10, 11, or 12 microns in the case of a wholly implanted sensor.
- “Dry film” thickness refers to the thickness of a cured film cast from a coating formulation onto the surface of the membrane by standard coating techniques.
- the electrode layer 50 or 147 is formed of a curable mixture of a urethane polymer and a hydrophilic polymer. Particularly preferred coatings are formed of a polyurethane polymer having anionic carboxylate functional groups and non-ionic hydrophilic polyether segments, which is crosslinked in the presence of polyvinylpyrrolidone and cured at a moderate temperature of about 50° C.
- the electrode layer 50 or 147 is formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like.
- the electrode layer 50 or 147 is formed from silicone polymer/hydrophilic polymer blends such as described above.
- an electrolyte phase is a free-fluid phase including a solution containing at least one compound, typically a soluble chloride salt, which conducts electric current.
- the electrolyte phase flows over the electrodes and is in contact with the electrolyte layer.
- the devices of the preferred embodiments contemplate the use of any suitable electrolyte solution, including standard, commercially available solutions.
- the electrolyte phase can have the same osmotic pressure or a lower osmotic pressure than the sample being analyzed.
- the electrolyte phase comprises normal saline.
- any of the layers discussed above can be omitted, altered, substituted for, and/or incorporated together.
- a distinct bioprotective layer may not exist.
- other domains accomplish the function of the bioprotective layer.
- the interference layer can be eliminated in certain embodiments wherein two-electrode differential measurements are employed to eliminate interference, for example, one electrode being sensitive to glucose and electrooxidizable interferants and the other only to interferants, such as is described in U.S. Pat. No. 6,514,718, which is incorporated herein by reference in its entirety.
- the interference layer can be omitted.
- the membrane system 18 comprises only two layers.
- One layer is the enzyme layer as described above.
- the second layer is positioned more distal than the enzyme layer and serves one or more of the functions described above for the cell disruptive layer, bioprotective layer, and diffusion resistance layer.
- this second layer is graduated either structurally and/or chemically as describe above such that different domains of the second layer serve different functions such as cell disruption, bio-protection, or diffusion resistance.
- both layers of this membrane system are formed from silicone polymer/hydrophilic polymer blends such as described above.
- every layer in the membrane system 18 is formed from silicone polymer/hydrophilic polymer blends such as described above. Such uniformity in ingredients allows for ease of manufacturing while at the same time allowing for tailoring of properties by varying the ratio of silicone polymer to hydrophilic polymer.
- PLURONIC® F-127 (PF-127) was dissolved under stirring in 100 g of anhydrous acetone at 40° C. 13 g of acetone was added to 37.3 g of the PF-127 solution followed by adding 4.8 g of dicumyl peroxide (DCP). 40 g of MED-4840 was mixed in a speed mixer at a speed of 3300 rpm for 60 seconds. The MED-4840 mixture was then placed in a motorized mechanical mixer equipped with a spiral dough hook. The mixture was stirred at low speed for 30 s. The stirring speed was then increased to medium-low and the PF-127/DCP solution was added at a rate of 3.5-4.0 g every 30 seconds.
- DCP dicumyl peroxide
- FIG. 6 is a graph depicting the resulting glucose sensor measurements over the course of approximately two months.
- the small points in FIG. 6 depict glucose concentrations measured by the sensor and the large points depict glucose concentrations measured by separate blood glucose assays. The graph indicates a close correlation between the sensor glucose measurements and the blood glucose measurements.
- a MED-4840/PLURONIC® F-127 membrane was manufactured using 20% PLURONIC® and a 20:1 ratio of DCP cross-linking agent per PLURONIC®. Prior to curing, the material was drawn down and a cell-disruptive porous silicone membrane was placed on the uncured layer. After curing, the combined bioprotective/porous silicone membrane was placed over a four-layer membrane having a diffusion resistance layer, enzyme layer, interference layer, and electrode layer. The combined membrane layers were placed on a wholly implantable glucose sensor. The sensor was sterilized and implanted into a diabetic rat model.
- FIG. 7 is a graph depicting the resulting glucose sensor measurements over the course of approximately two months. The small points in FIG. 7 depict glucose concentrations measured by the sensor and the large points depict glucose concentrations measured by separate blood glucose assays. The graph indicates a close correlation between the sensor glucose measurements and the blood glucose measurements.
- a MED-4840/PLURONIC® F-127 membrane was manufactured using 8.4% PLURONIC® and 3.7% DCP. This membrane was placed over two-layer membrane having an electrode layer and an enzyme layer. The combined membrane layers were installed on a wholly implantable glucose sensor.
- the sensor was placed into a 2 L bath filled with PBS (saline). The continuously stirred bath was brought to 37° C. and the sensor allowed to equilibrate for a minimum of 1 hour until the sensors reached a flat line continuous baseline signal. Acetaminophen was then added to the bath to a dilution of 3.8 mg/dl. The sensor was then allowed to equilibrate over 1 hour while measurements were continuously recorded from the sensor.
- FIG. 8 is a graph show the sensor signal over the course of the hour. The graph indicates that the signal changed by less than 1%. Thus, the sensor was substantially insensitive to the presence of acetaminophen, indicating that the membrane substantially reduces transport of acetaminophen therethrough.
- a wholly implantable glucose sensor with a membrane not including a silicone/hydrophilic-hydrophobic polymer blend was tested.
- the membrane in this sensor included a three-layer membrane having an electrode layer, an enzyme layer, and a polyurethane diffusion resistance layer.
- a porous silicone cell disruptive layer was added on top.
- the sensor was placed into a 2 L bath filled with PBS (saline). The continuously stirred bath was brought to 37° C. and the sensor allowed to equilibrate for a minimum of 1 hour until the sensors reached a flat line continuous baseline signal. Acetaminophen was then added to the bath to a dilution of 3.8 mg/dl.
- FIG. 9 is a graph show the sensor signal over the course of the hour. The graph indicates that the signal changed by more than 15% after introduction of the acetaminophen. Thus, without the silicone/hydrophilic-hydrophobic polymer blend sensor was sensitive to the acetaminophen interferant.
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Abstract
Membrane systems incorporating silicone polymers are described for use in implantable analyte sensors. Some layers of the membrane system may comprise a blend of a silicone polymer with a hydrophilic polymer, for example, a triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. Such polymeric blends provide for both high oxygen solubility and aqueous analyte solubility.
Description
- Any and all priority claims identified in the Application Data Sheet, or any correction thereto, are hereby incorporated by reference under 37 CFR 1.57. This application is a continuation of U.S. application Ser. No. 16/039,178, filed Jul. 18, 2018, which is a continuation of U.S. application Ser. No. 15/796,163, filed Oct. 27, 2017, now U.S. Pat. No. 10,052,051, which is a continuation of U.S. application Ser. No. 15/377,443, filed Dec. 13, 2016, now abandoned, which is a continuation of U.S. application Ser. No. 13/951,358, filed Jul. 25, 2013, now U.S. Pat. No. 9,549,693, which is a continuation of U.S. application Ser. No. 13/277,997, filed Oct. 20, 2011, now U.S. Pat. No. 8,543,184, which is a continuation of U.S. application Ser. No. 12/511,982, filed Jul. 29, 2009, now U.S. Pat. No. 8,064,977, which is a divisional of U.S. application Ser. No. 11/404,417, filed Apr. 14, 2006, now U.S. Pat. No. 7,613,491. Each of the aforementioned applications is incorporated by reference herein in its entirety, and each is hereby expressly made a part of this specification.
- The invention relates to membranes for use in implantable analyte sensors (e.g., glucose sensors).
- Electrochemical sensors are useful in chemistry and medicine to determine the presence or concentration of a biological analyte. Such sensors are useful, for example, to monitor glucose in diabetic patients and lactate during critical care events.
- Diabetes mellitus is a disorder in which the pancreas cannot create sufficient insulin (Type I or insulin dependent) and/or in which insulin is not effective (
Type 2 or non-insulin dependent). In the diabetic state, the victim suffers from high blood sugar, which causes an array of physiological derangements (kidney failure, skin ulcers, or bleeding into the vitreous of the eye) associated with the deterioration of small blood vessels. A hypoglycemic reaction (low blood sugar) is induced by an inadvertent overdose of insulin, or after a normal dose of insulin or glucose-lowering agent accompanied by extraordinary exercise or insufficient food intake. - Conventionally, a diabetic person carries a self-monitoring blood glucose (SMBG) monitor, which typically utilizes uncomfortable finger pricking methods. Due to the lack of comfort and convenience, a diabetic normally only measures his or her glucose level two to four times per day. Unfortunately, these time intervals are spread so far apart that the diabetic likely finds out too late, sometimes incurring dangerous side effects, of a hyperglycemic or hypoglycemic condition. In fact, it is not only unlikely that a diabetic will take a timely SMBG value, but additionally the diabetic will not know if their blood glucose value is going up (higher) or down (lower) based on conventional methods.
- Consequently, a variety of transdermal and implantable electrochemical sensors are being developed for continuously detecting and/or quantifying blood glucose values. Many implantable glucose sensors suffer from complications within the body and provide only short-term or less-than-accurate sensing of blood glucose. Similarly, transdermal sensors have problems in accurately sensing and reporting back glucose values continuously over extended periods of time. Some efforts have been made to obtain blood glucose data from implantable devices and retrospectively determine blood glucose trends for analysis; however these efforts do not aid the diabetic in determining real-time blood glucose information. Some efforts have also been made to obtain blood glucose data from transdermal devices for prospective data analysis, however similar problems have been observed.
- One embodiment disclosed herein includes a membrane for use in an analyte sensor, the membrane including a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer, wherein the membrane is adapted to permit diffusion of both the analyte and oxygen therethrough. In one embodiment, the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer. In one embodiment, the silicone elastomer comprises vinyl substituents. In one embodiment, the silicone elastomer is an elastomer produced by curing a MED-4840 mixture. In one embodiment, the copolymer comprises hydroxy substituents. In one embodiment, the co-polymer is a triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In one embodiment, the co-polymer is a triblock poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In one embodiment, the co-polymer is a PLURONIC® polymer. In one embodiment, the co-polymer is PLURONIC® F-127. In one embodiment, the analyte is glucose. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of the membrane is the co-polymer.
- Another embodiment disclosed herein includes an implantable analyte sensor having an enzyme layer comprising an enzyme for which the analyte is a substrate and a bioprotective layer positioned between the enzyme layer and tissue adjacent to the sensor when implanted, wherein the bioprotective layer comprises a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer. One embodiment further includes a diffusion resistance layer positioned between the enzyme layer and the bioprotective layer. In one embodiment, the diffusion resistance layer also comprises the silicone elastomer and the poly(ethylene oxide) and poly(propylene oxide) co-polymer. In one embodiment, the ratio of the silicone elastomer to the co-polymer is different in the diffusion resistance layer than in the bioprotective layer. One embodiment further includes a cell disruptive layer positioned between the bioprotective layer and tissue adjacent to the sensor when implanted. In one embodiment, the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer. In one embodiment, the silicone elastomer comprises vinyl substituents. In one embodiment, the silicone elastomer is an elastomer produced by curing a MED-4840 mixture. In one embodiment, the copolymer comprises hydroxy substituents. In one embodiment, the co-polymer is a triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In one embodiment, the co-polymer is a triblock poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In one embodiment, the co-polymer is a PLURONIC® polymer. In one embodiment, the co-polymer is PLURONIC® F-127. In one embodiment, the analyte is glucose. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of the bioprotective layer is the co-polymer. In one embodiment, the enzyme layer also comprises the silicone elastomer and the co-polymer. In one embodiment, the ratio of the silicone elastomer to the co-polymer is different in the enzyme layer than in the bioprotective layer. In one embodiment, the sensor is configured to be wholly implanted. In one embodiment, the sensor is configured to be transcutaneously implanted. In one embodiment, at least a portion of the bioprotective layer is porous and adjacent to tissue when implanted.
- Another embodiment disclosed herein includes an implantable analyte sensor having an enzyme layer comprising an enzyme for which the analyte is a substrate and a diffusion resistance layer comprising a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer, wherein the diffusion resistance layer is positioned between the enzyme layer and tissue adjacent to the sensor when implanted. One embodiment further includes a bioprotective layer positioned between the diffusion resistance layer and tissue adjacent to the sensor when implanted. In one embodiment, the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer. In one embodiment, the silicone elastomer comprises vinyl substituents. In one embodiment, the silicone elastomer is an elastomer produced by curing a MED-4840 mixture. In one embodiment, the copolymer comprises hydroxy substituents. In one embodiment, the co-polymer is a PLURONIC® polymer. In one embodiment, the co-polymer is PLURONIC® F-127. In one embodiment, the analyte is glucose. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of the diffusion resistance layer is the co-polymer. In one embodiment, the ratio of the silicone elastomer to co-polymer varies within the diffusion resistance layer. In one embodiment, the sensor is configured to be wholly implanted. In one embodiment, the sensor is configured to be transcutaneously implanted.
- Another embodiment disclosed herein includes an implantable analyte sensor having at least one polymer membrane, wherein every polymer membrane in the sensor comprises a silicone elastomer and a poly(ethylene oxide) and poly(propylene oxide) co-polymer. In one embodiment, the silicone elastomer is a dimethyl- and methylhydrogen-siloxane copolymer. In one embodiment, the silicone elastomer comprises vinyl substituents. In one embodiment, the silicone elastomer is an elastomer produced by curing a MED-4840 mixture. In one embodiment, the copolymer comprises hydroxy substituents. In one embodiment, the co-polymer is a PLURONIC® polymer. In one embodiment, the co-polymer is PLURONIC® F-127. In one embodiment, at least a portion of the co-polymer is cross-linked. In one embodiment, from about 5% w/w to about 30% w/w of each polymer membrane is the co-polymer. In one embodiment, the sensor comprises at least two polymer membranes having a ratio of the silicone elastomer to the co-polymer that is different. In one embodiment, the sensor is configured to be wholly implanted. In one embodiment, the sensor is configured to be transcutaneously implanted.
- Another embodiment disclosed herein includes a method of manufacturing a membrane for use in an analyte sensor, the method including mixing a precursor of a silicone elastomer with a poly(ethylene oxide) and poly(propylene oxide) co-polymer and heating the mixture. In one embodiment, the ratio of co-polymer to silicone elastomer that is mixed is from about 1:20 w/w to about 1:4 w/w. One embodiment further includes mixing the co-polymer with a cross-linking agent. In one embodiment, the cross-linking agent is mixed with the co-polymer prior to mixing the co-polymer with the silicone elastomer precursor. In one embodiment, the cross-linking agent is selected from the group consisting of one or more of ethylene glycol diglycidyl ether and poly(ethylene glycol) diglycidyl ether. In one embodiment, the cross-linking agent comprises dicumyl peroxide. In one embodiment, the ratio of cross-linking agent to co-polymer is from about 10 cross-linking agent molecules per co-polymer molecule to about 30 cross-linking agent molecules per co-polymer molecule. In one embodiment, the amount of cross-linking agent added relative to the silicone elastomer and co-polymer is from about 0.5% to about 15% w/w. One embodiment further includes, after the mixing step but before the heating step, drawing the mixture into a thin film. One embodiment further includes, after the drawing step but before the heating step, placing a piece of porous silicon on the thin film.
-
FIG. 1 is an exploded perspective view of an implantable glucose sensor in one exemplary embodiment. -
FIG. 2 is a block diagram that illustrates the sensor electronics in one embodiment; however a variety of sensor electronics configurations can be implemented with the preferred embodiments. -
FIG. 3 is a perspective view of a transcutaneous wire analyte sensor system. -
FIG. 4 is a schematic illustration of a membrane system of the device ofFIG. 1 . -
FIG. 5 is a cross-sectional view through the sensor ofFIG. 3 on line C-C, showing an exposed electroactive surface of a working electrode surrounded by a membrane system. -
FIG. 6 is a graph depicting glucose measurements from a sensor including a silicon/hydrophilic-hydrophobic polymer blend in a diffusion resistance layer implanted in a diabetic rat model. -
FIG. 7 is a graph depicting glucose measurements from a sensor including a silicon/hydrophilic-hydrophobic polymer blend in a bioprotective layer implanted in a diabetic rat model. -
FIG. 8 is a graph depicting a sensor signal from a sensor including a silicon/hydrophilic-hydrophobic polymer blend membrane exposed to acetaminophen. -
FIG. 9 is a graph depicting a sensor signal from a sensor not including a silicon/hydrophilic-hydrophobic polymer blend membrane exposed to acetaminophen. - The following description and examples illustrate some exemplary embodiments of the disclosed invention in detail. Those of skill in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope. Accordingly, the description of a certain exemplary embodiment should not be deemed to limit the scope of the present invention.
- In order to facilitate an understanding of the preferred embodiments, a number of terms are defined below.
- The term “analyte” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a substance or chemical constituent in a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the sensing regions, devices, and methods is glucose. However, other analytes are contemplated as well, including but not limited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-ß hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free ß-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, ß); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanic/pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids can also constitute analytes in certain embodiments. The analyte can be naturally present in the biological fluid or endogenous, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte can be introduced into the body or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals generated within the body can also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA).
- The terms “operable connection,” “operably connected,” and “operably linked” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to one or more components linked to another component(s) in a manner that allows transmission of signals between the components. For example, one or more electrodes can be used to detect the amount of analyte in a sample and convert that information into a signal; the signal can then be transmitted to a circuit. In this case, the electrode is “operably linked” to the electronic circuitry.
- The term “host” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to animals and plants, for example humans.
- The terms “electrochemically reactive surface” and “electroactive surface” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to the surface of an electrode where an electrochemical reaction takes place. As one example, a working electrode measures hydrogen peroxide produced by the enzyme catalyzed reaction of the analyte being detected reacts creating an electric current (for example, detection of glucose analyte utilizing glucose oxidase produces H2O2 as a by product, H2O2 reacts with the surface of the working electrode producing two protons (2H+), two electrons (2e−) and one molecule of oxygen (O2) which produces the electronic current being detected). In the case of the counter electrode, a reducible species, for example, O2 is reduced at the electrode surface in order to balance the current being generated by the working electrode.
- The term “sensing region” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the region of a monitoring device responsible for the detection of a particular analyte. The sensing region generally comprises a non-conductive body, a working electrode, a reference electrode, and/or a counter electrode (optional) passing through and secured within the body forming electrochemically reactive surfaces on the body, an electronic connective means at another location on the body, and a multi-domain membrane affixed to the body and covering the electrochemically reactive surface.
- The terms “raw data stream” and “data stream” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to an analog or digital signal directly related to the measured glucose concentration from the glucose sensor. In one example, the raw data stream is digital data in “counts” converted by an A/D converter from an analog signal (for example, voltage or amps) representative of a glucose concentration. The terms broadly encompass a plurality of time spaced data points from a substantially continuous glucose sensor, which comprises individual measurements taken at time intervals ranging from fractions of a second up to, for example, 1, 2, or 5 minutes or longer.
- The term “counts” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a unit of measurement of a digital signal. In one example, a raw data stream measured in counts is directly related to a voltage (for example, converted by an A/D converter), which is directly related to current from the working electrode. In another example, counter electrode voltage measured in counts is directly related to a voltage.
- The term “electrical potential” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the electrical potential difference between two points in a circuit which is the cause of the flow of a current.
- The term “ischemia” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to local and temporary deficiency of blood supply due to obstruction of circulation to a part (for example, sensor). Ischemia can be caused by mechanical obstruction (for example, arterial narrowing or disruption) of the blood supply, for example.
- The term “system noise” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to unwanted electronic or diffusion-related noise which can include Gaussian, motion-related, flicker, kinetic, or other white noise, for example.
- The terms “signal artifacts” and “transient non-glucose related signal artifacts,” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to signal noise that is caused by substantially non-glucose reaction rate-limiting phenomena, such as ischemia, pH changes, temperature changes, pressure, and stress, for example. Signal artifacts, as described herein, are typically transient and are characterized by higher amplitude than system noise.
- The terms “low noise” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to noise that substantially decreases signal amplitude.
- The terms “high noise” and “high spikes” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to noise that substantially increases signal amplitude.
- The term “silicone composition” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a composition of matter that comprises polymers having at least silicon and oxygen atoms in the backbone.
- The phrase “distal to” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference. For example, some embodiments of a device include a membrane system having a cell disruptive domain and a cell impermeable domain. If the sensor is deemed to be the point of reference and the cell disruptive domain is positioned farther from the sensor, then that domain is distal to the sensor.
- The phrase “proximal to” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to the spatial relationship between various elements in comparison to a particular point of reference. For example, some embodiments of a device include a membrane system having a cell disruptive domain and a cell impermeable domain. If the sensor is deemed to be the point of reference and the cell impermeable domain is positioned nearer to the sensor, then that domain is proximal to the sensor.
- The terms “interferants” and “interfering species” as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to effects and/or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. In an exemplary electrochemical sensor, interfering species can include compounds with an oxidation potential that overlaps with that of the analyte to be measured.
- As employed herein, the following abbreviations apply: Eq and Eqs (equivalents); mEq (milliequivalents); M (molar); mM (millimolar) μM (micromolar); N (Normal); mol (moles); mmol (millimoles); μmol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); μg (micrograms); Kg (kilograms); L (liters); mL (milliliters); dL (deciliters); μL (microliters); cm (centimeters); mm (millimeters); μm (micrometers); nm (nanometers); h and hr (hours); min. (minutes); s and sec. (seconds); ° C. (degrees Centigrade).
- Membrane systems of the preferred embodiments are suitable for use with implantable devices in contact with a biological fluid. For example, the membrane systems can be utilized with implantable devices such as devices for monitoring and determining analyte levels in a biological fluid, for example, glucose levels for individuals having diabetes. In some embodiments, the analyte-measuring device is a continuous device. Alternatively, the device can analyze a plurality of intermittent biological samples. The analyte-measuring device can use any method of analyte-measurement, including enzymatic, chemical, physical, electrochemical, spectrophotometric, polarimetric, calorimetric, radiometric, or the like.
- Although some of the description that follows is directed at glucose-measuring devices, including the described membrane systems and methods for their use, these membrane systems are not limited to use in devices that measure or monitor glucose. These membrane systems are suitable for use in a variety of devices, including, for example, those that detect and quantify other analytes present in biological fluids (including, but not limited to, cholesterol, amino acids, alcohol, galactose, and lactate), cell transplantation devices (see, for example, U.S. Pat. Nos. 6,015,572, 5,964,745, and 6,083,523), drug delivery devices (see, for example, U.S. Pat. Nos. 5,458,631, 5,820,589, and 5,972,369), and the like. Preferably, implantable devices that include the membrane systems of the preferred embodiments are implanted in soft tissue, for example, abdominal, subcutaneous, and peritoneal tissues, the brain, the intramedullary space, and other suitable organs or body tissues.
- In addition to the glucose-measuring device described below, the membrane systems of the preferred embodiments can be employed with a variety of known glucose measuring-devices. In some embodiments, the electrode system can be used with any of a variety of known in vivo analyte sensors or monitors, such as U.S. Pat. No. 6,001,067 to Shults et al.; U.S. Pat. No. 6,702,857 to Brauker et al.; U.S. Pat. No. 6,212,416 to Ward et al.; U.S. Pat. No. 6,119,028 to Schulman et al.; U.S. Pat. No. 6,400,974 to Lesho; U.S. Pat. No. 6,595,919 to Berner et al.; U.S. Pat. No. 6,141,573 to Kurnik et al.; U.S. Pat. No. 6,122,536 to Sun et al.; European Patent Application EP 1153571 to Varall et al.; U.S. Pat. No. 6,512,939 to Colvin et al.; U.S. Pat. No. 5,605,152 to Slate et al.; U.S. Pat. No. 4,431,004 to Bessman et al.; U.S. Pat. No. 4,703,756 to Gough et al.; U.S. Pat. No. 6,514,718 to Heller et al.; U.S. Pat. No. 5,985,129 to Gough et al.; WO Patent Application Publication No. 04/021877 to Caduff; U.S. Pat. No. 5,494,562 to Maley et al.; U.S. Pat. No. 6,120,676 to Heller et al.; and U.S. Pat. No. 6,542,765 to Guy et al., each of which are incorporated in there entirety herein by reference. In general, it is understood that the disclosed embodiments are applicable to a variety of continuous glucose measuring device configurations.
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FIG. 1 is an exploded perspective view of one exemplary embodiment comprising animplantable glucose sensor 10 that utilizes amperometric electrochemical sensor technology to measure glucose. In this exemplary embodiment, a body 12 with asensing region 14 includes anelectrode system 16 and sensor electronics, which are described in more detail with reference toFIG. 2 . - In this embodiment, the
electrode system 16 is operably connected to the sensor electronics (FIG. 2 ) and includes electroactive surfaces, which are covered by amembrane system 18. Themembrane system 18 is disposed over the electroactive surfaces of theelectrode system 16 and provides one or more of the following functions: 1) supporting tissue ingrowth (cell disruptive domain); 2) protection of the exposed electrode surface from the biological environment (cell impermeable domain); 3) diffusion resistance (limitation) of the analyte (resistance domain); 4) a catalyst for enabling an enzymatic reaction (enzyme domain); 5) limitation or blocking of interfering species (interference domain); and/or 6) hydrophilicity at the electrochemically reactive surfaces of the sensor interface (electrolyte domain), for example, as described in co-pending U.S. patent application Ser. No. 10/838,912, filed May 3, 2004, published in Publication No. 20050245799, and entitled “IMPLANTABLE ANALYTE SENSOR,” the contents of which are hereby incorporated herein by reference in their entirety. The membrane system can be attached to the sensor body 12 by mechanical or chemical methods, for example, such as is described in the co-pending application Ser. No. 10/838,912 mentioned above. - The
membrane system 18 of the preferred embodiments, which are described in more detail below with reference toFIGS. 5 and 6 , is formed at least partially from silicone materials. While not being bound by any particular theory, it is believed that silicone materials provide enhanced bio-stability when compared to other polymeric materials such as polyurethane. In addition, when a porous silicone cell disruptive layer (described in detail below) is used, silicone included in any underlying layer can promote bonding of the layer to the porous silicone cell disruptive layer. Finally, silicone has high oxygen permeability, thus promoting oxygen transport to the enzyme layer (described in detail below). - In some embodiments, the
electrode system 16, which is located on or within thesensing region 14, is comprised of at least a working and a reference electrode with an insulating material disposed therebetween. In some alternative embodiments, additional electrodes can be included within the electrode system, for example, a three-electrode system (working, reference, and counter electrodes) and/or including an additional working electrode (which can be used to generate oxygen, measure an additional analyte, or can be configured as a baseline subtracting electrode, for example). - In the exemplary embodiment of
FIG. 1 , the electrode system includes three electrodes (working, counter, and reference electrodes), wherein the counter electrode is provided to balance the current generated by the species being measured at the working electrode. In the case of a glucose oxidase based glucose sensor, the species being measured at the working electrode is H2O2. Glucose oxidase, GOX, catalyzes the conversion of oxygen and glucose to hydrogen peroxide and gluconate according to the following reaction: -
GOX+Glucose+O2→Gluconate+H2O2+reduced GOX - The change in H2O2 can be monitored to determine glucose concentration because for each glucose molecule metabolized, there is a proportional change in the product H2O2. Oxidation of H2O2 by the working electrode is balanced by reduction of ambient oxygen, enzyme generated H2O2, or other reducible species at the counter electrode. The H2O2 produced from the glucose oxidase reaction further reacts at the surface of working electrode and produces two protons (2H+), two electrons (2e−), and one oxygen molecule (O2). In such embodiments, because the counter electrode utilizes oxygen as an electron acceptor, the most likely reducible species for this system are oxygen or enzyme generated peroxide. There are two main pathways by which oxygen can be consumed at the counter electrode. These pathways include a four-electron pathway to produce hydroxide and a two-electron pathway to produce hydrogen peroxide. In addition to the counter electrode, oxygen is further consumed by the reduced glucose oxidase within the enzyme domain. Therefore, due to the oxygen consumption by both the enzyme and the counter electrode, there is a net consumption of oxygen within the electrode system. Theoretically, in the domain of the working electrode there is significantly less net loss of oxygen than in the region of the counter electrode. In addition, there is a close correlation between the ability of the counter electrode to maintain current balance and sensor function.
- In general, in electrochemical sensors wherein an enzymatic reaction depends on oxygen as a co-reactant, depressed function or inaccuracy can be experienced in low oxygen environments, for example in vivo. Subcutaneously implanted devices are especially susceptible to transient ischemia that can compromise device function; for example, because of the enzymatic reaction required for an implantable amperometric glucose sensor, oxygen must be in excess over glucose in order for the sensor to effectively function as a glucose sensor. If glucose becomes in excess, the sensor turns into an oxygen sensitive device. In vivo, glucose concentration can vary from about one hundred times or more that of the oxygen concentration. Consequently, oxygen becomes a limiting reactant in the electrochemical reaction and when insufficient oxygen is provided to the sensor, the sensor is unable to accurately measure glucose concentration. Those skilled in the art interpret oxygen limitations resulting in depressed function or inaccuracy as a problem of availability of oxygen to the enzyme and/or counter electrode. Oxygen limitations can also be seen during periods of transient ischemia that occur, for example, under certain postures or when the region around the implanted sensor is compressed so that blood is forced out of the capillaries. Such ischemic periods observed in implanted sensors can last for many minutes or even an hour or longer.
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FIG. 2 is a block diagram that illustrates the sensor electronics in one embodiment. In this embodiment, apotentiostat 134 is shown, which is operably connected to an electrode system (such as described above) and provides a voltage to the electrodes, which biases the sensor to enable measurement of an current signal indicative of the analyte concentration in the host (also referred to as the analog portion). In some embodiments, the potentiostat includes a resistor (not shown) that translates the current into voltage. In some alternative embodiments, a current to frequency converter is provided that is configured to continuously integrate the measured current, for example, using a charge counting device. - An A/
D converter 136 digitizes the analog signal into a digital signal, also referred to as “counts” for processing. Accordingly, the resulting raw data stream in counts, also referred to as raw sensor data, is directly related to the current measured by thepotentiostat 134. - A
processor module 138 includes the central control unit that controls the processing of thesensor electronics 132. In some embodiments, the processor module includes a microprocessor, however a computer system other than a microprocessor can be used to process data as described herein, for example an ASIC can be used for some or all of the sensor's central processing. The processor typically provides semi-permanent storage of data, for example, storing data such as sensor identifier (ID) and programming to process data streams (for example, programming for data smoothing and/or replacement of signal artifacts such as is described in U.S. Publication No. US-2005-0043598-A1). The processor additionally can be used for the system's cache memory, for example for temporarily storing recent sensor data. In some embodiments, the processor module comprises memory storage components such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flash memory, or the like. - In some embodiments, the processor module comprises a digital filter, for example, an infinite impulse response (IIR) or finite impulse response (FIR) filter, configured to smooth the raw data stream from the A/D converter. Generally, digital filters are programmed to filter data sampled at a predetermined time interval (also referred to as a sample rate). In some embodiments, wherein the potentiostat is configured to measure the analyte at discrete time intervals, these time intervals determine the sample rate of the digital filter. In some alternative embodiments, wherein the potentiostat is configured to continuously measure the analyte, for example, using a current-to-frequency converter as described above, the processor module can be programmed to request a digital value from the A/D converter at a predetermined time interval, also referred to as the acquisition time. In these alternative embodiments, the values obtained by the processor are advantageously averaged over the acquisition time due the continuity of the current measurement. Accordingly, the acquisition time determines the sample rate of the digital filter. In preferred embodiments, the processor module is configured with a programmable acquisition time, namely, the predetermined time interval for requesting the digital value from the A/D converter is programmable by a user within the digital circuitry of the processor module. An acquisition time of from about 2 seconds to about 512 seconds is preferred; however any acquisition time can be programmed into the processor module. A programmable acquisition time is advantageous in optimizing noise filtration, time lag, and processing/battery power.
- Preferably, the processor module is configured to build the data packet for transmission to an outside source, for example, an RF transmission to a receiver as described in more detail below. Generally, the data packet comprises a plurality of bits that can include a preamble, a unique identifier identifying the electronics unit, the receiver, or both, (e.g., sensor ID code), data (e.g., raw data, filtered data, and/or an integrated value) and/or error detection or correction. Preferably, the data (transmission) packet has a length of from about 8 bits to about 128 bits, preferably about 48 bits; however, larger or smaller packets can be desirable in certain embodiments. The processor module can be configured to transmit any combination of raw and/or filtered data. In one exemplary embodiment, the transmission packet contains a fixed preamble, a unique ID of the electronics unit, a single five-minute average (e.g., integrated) sensor data value, and a cyclic redundancy code (CRC).
- In some embodiments, the processor module further comprises a transmitter portion that determines the transmission interval of the sensor data to a receiver, or the like. In some embodiments, the transmitter portion, which determines the interval of transmission, is configured to be programmable. In one such embodiment, a coefficient can be chosen (e.g., a number of from about 1 to about 100, or more), wherein the coefficient is multiplied by the acquisition time (or sampling rate), such as described above, to define the transmission interval of the data packet. Thus, in some embodiments, the transmission interval is programmable from about 2 seconds to about 850 minutes, more preferably from about 30 second to about 5 minutes; however, any transmission interval can be programmable or programmed into the processor module. However, a variety of alternative systems and methods for providing a programmable transmission interval can also be employed. By providing a programmable transmission interval, data transmission can be customized to meet a variety of design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.)
- Conventional glucose sensors measure current in the nanoAmp range. In some embodiments, the preferred embodiments are configured to measure the current flow in the picoAmp range, and in some embodiments, femtoAmps. Namely, for every unit (mg/dL) of glucose measured, at least one picoAmp of current is measured. Preferably, the analog portion of the A/
D converter 136 is configured to continuously measure the current flowing at the working electrode and to convert the current measurement to digital values representative of the current. In one embodiment, the current flow is measured by a charge counting device (e.g., a capacitor). Preferably, a charge counting device provides a value (e.g., digital value) representative of the current flow integrated over time (e.g., integrated value). In some embodiments, the value is integrated over a few seconds, a few minutes, or longer. In one exemplary embodiment, the value is integrated over 5 minutes; however, other integration periods can be chosen. Thus, a signal is provided, whereby a high sensitivity maximizes the signal received by a minimal amount of measured hydrogen peroxide (e.g., minimal glucose requirements without sacrificing accuracy even in low glucose ranges), reducing the sensitivity to oxygen limitations in vivo (e.g., in oxygen-dependent glucose sensors). - In some embodiments, the electronics unit is programmed with a specific ID, which is programmed (automatically or by the user) into a receiver to establish a secure wireless communication link between the electronics unit and the receiver. Preferably, the transmission packet is Manchester encoded; however, a variety of known encoding techniques can also be employed.
- A
battery 154 is operably connected to thesensor electronics 132 and provides the power for the sensor. In one embodiment, the battery is a lithium manganese dioxide battery; however, any appropriately sized and powered battery can be used (for example, AAA, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion, zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed). In some embodiments, the battery is rechargeable, and/or a plurality of batteries can be used to power the system. The sensor can be transcutaneously powered via an inductive coupling, for example. In some embodiments, a quartz crystal 96 is operably connected to theprocessor 138 and maintains system time for the computer system as a whole, for example for the programmable acquisition time within the processor module. - Optional temperature probe 140 is shown, wherein the temperature probe is located on the electronics assembly or the glucose sensor itself. The temperature probe can be used to measure ambient temperature in the vicinity of the glucose sensor. This temperature measurement can be used to add temperature compensation to the calculated glucose value.
- An
RF module 158 is operably connected to theprocessor 138 and transmits the sensor data from the sensor to a receiver within awireless transmission 160 viaantenna 152. In some embodiments, asecond quartz crystal 154 provides the time base for the RF carrier frequency used for data transmissions from the RF transceiver. In some alternative embodiments, however, other mechanisms, such as optical, infrared radiation (IR), ultrasonic, or the like, can be used to transmit and/or receive data. - In the RF telemetry module of the preferred embodiments, the hardware and software are designed for low power requirements to increase the longevity of the device (for example, to enable a life of from about 3 to about 24 months, or more) with maximum RF transmittance from the in vivo environment to the ex vivo environment for wholly implantable sensors (for example, a distance of from about one to ten meters or more). Preferably, a high frequency carrier signal of from about 402 MHz to about 433 MHz is employed in order to maintain lower power requirements. In some embodiments, the RF module employs a one-way RF communication link to provide a simplified ultra low power data transmission and receiving scheme. The RF transmission can be OOK or FSK modulated, preferably with a radiated transmission power (EIRP) fixed at a single power level of typically less than about 100 microwatts, preferably less than about 75 microwatts, more preferably less than about 50 microwatts, and most preferably less than about 25 microwatts.
- Additionally, in wholly implantable devices, the carrier frequency may be adapted for physiological attenuation levels, which is accomplished by tuning the RF module in a simulated in vivo environment to ensure RF functionality after implantation; accordingly, the preferred glucose sensor can sustain sensor function for 3 months, 6 months, 12 months, or 24 months or more.
- The above description of sensor electronics associated with the electronics unit is applicable to a variety of continuous analyte sensors, such as non-invasive, minimally invasive, and/or invasive (e.g., transcutaneous and wholly implantable) sensors. For example, the sensor electronics and data processing as well as the receiver electronics and data processing described below can be incorporated into the wholly implantable glucose sensor disclosed in U.S. Publication No. US-2005-0245799-A1 and U.S. patent application Ser. No. 10/885,476 filed Jul. 6, 2004 and entitled, “SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM.”
- In one alternative embodiment, rather than the sensor being wholly implanted, a transcutaneous wire sensor is utilized. For example, one such
suitable wire sensor 142 is depicted inFIG. 3 . This sensor comprises a platinumwire working electrode 144 with insulating coating 145 (e.g., parylene). A silver or silver/silver chloridereference electrode wire 146 is helically wound around the insulatingcoating 145. A portion of the insulatingcoating 145 is removed to create an exposedelectroactive window 143 around which a membrane as described herein can be disposed. Further details regarding such wire sensors may be found in U.S application Ser. No. 11/157,746, filed Jun. 21, 2005 and entitled “TRANSCUTANEOUS ANALYTE SENSOR,” which is incorporated herein by reference in its entirety. - As described below with reference to
FIG. 4 , themembrane system 18 can include two or more layers that cover an implantable device, for example, an implantable glucose sensor. Similarly, as described below with reference toFIG. 5 , two or more layers of the membrane system may be disposed on a transcutaneous wire sensor. In the example of an implantable enzyme-based electrochemical glucose sensor, the membrane prevents direct contact of the biological fluid sample with the electrodes, while controlling the permeability of selected substances (for example, oxygen and glucose) present in the biological fluid through the membrane for reaction in an enzyme rich domain with subsequent electrochemical reaction of formed products at the electrodes. - The membrane systems of preferred embodiments are constructed of one or more membrane layers. Each distinct layer can comprise the same or different materials. Furthermore, each layer can be homogenous or alternatively may comprise different domains or gradients where the composition varies.
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FIG. 4 is an illustration of a membrane system in one preferred embodiment. Themembrane system 18 can be used with a glucose sensor such, as is described above with reference toFIG. 1 . In this embodiment, themembrane system 18 includes a celldisruptive layer 40 most distal of all domains from the electrochemically reactive surfaces, abioprotective layer 42 less distal from the electrochemically reactive surfaces than the cell disruptive layer, adiffusion resistance layer 44 less distal from the electrochemically reactive surfaces than the bioprotective layer, anenzyme layer 46 less distal from the electrochemically reactive surfaces than the diffusion resistance layer, aninterference layer 48 less distal from the electrochemically reactive surfaces than the enzyme layer, and anelectrode layer 50 adjacent to the electrochemically reactive surfaces. However, it is understood that the membrane system can be modified for use in other devices, by including only two or more of the layers, or additional layers not recited above. -
FIG. 5 is an illustration of a membrane system in one preferred embodiment of a transcutaneous wire sensor.FIG. 5 is a cross-sectional view through the sensor ofFIG. 3 on line C-C. In this embodiment, the membrane system includes anelectrode layer 147, aninterference layer 148, andenzyme layer 149, and adiffusion resistance layer 150 wrapped around the platinumwire working electrode 144. In some embodiments, this membrane system also includes a cell impermeable layer as described below. In some embodiments, the transcutaneous wire sensor is configured for short-term implantation (e.g., 1-30 days). Accordingly, in these embodiments, the cell disruptive layer may not be required because a foreign body capsule does not form in the short duration of implantation. - In some embodiments, the membrane systems for use in implantable sensors is formed as a physically continuous membrane, namely, a membrane having substantially uniform physical structural characteristics from one side of the membrane to the other. However, the membrane can have chemically heterogeneous domains, for example, domains resulting from the use of block copolymers (for example, polymers in which different blocks of identical monomer units alternate with each other), but can be defined as homogeneous overall in that each of the above-described layers functions by the preferential diffusion of some substance through the homogeneous membrane.
- Some layers of the
membrane systems 18 of the preferred embodiments include materials with high oxygen solubility. In some embodiments, themembrane systems 18 with high oxygen solubility simultaneously permit efficient transport of aqueous solutions of the analyte. - In one embodiment, one or more layer(s) is/are formed from a composition that, in addition to providing high oxygen solubility, allows for the transport of glucose or other such water-soluble molecules (for example, drugs). In one embodiment, these layers comprise a blend of a silicone polymer with a hydrophilic polymer. By “hydrophilic polymer,” it is meant that the polymer has a substantially hydrophilic domain in which aqueous substances can easily dissolve. In one embodiment, the hydrophilic polymer has a molecular weight of at least about 1000 g/mol, 5,000 g/mol, 8,000 g/mol, 10,000 g/mol, or 15,000 g/mol. In one embodiment, the hydrophilic polymer comprises both a hydrophilic domain and a partially hydrophobic domain (e.g., a copolymer). The hydrophobic domain(s) facilitate the blending of the hydrophilic polymer with the hydrophobic silicone polymer. In one embodiment, the hydrophobic domain is itself a polymer (i.e., a polymeric hydrophobic domain). For example, in one embodiment, the hydrophobic domain is not a simple molecular head group but is rather polymeric. In various embodiments, the molecular weight of any covalently continuous hydrophobic domain within the hydrophilic polymer is at least about 500 g/mol, 700 g/mol, 1000 g/mol, 2000 g/mol, 5000 g/mol, or 8,000 g/mol. In various embodiments, the molecular weight of any covalently continuous hydrophilic domain within the hydrophilic polymer is at least about 500 g/mol, 700 g/mol, 1000 g/mol, 2000 g/mol, 5000 g/mol, or 8,000 g/mol.
- In various embodiments, the ratio of the silicone polymer to hydrophilic polymer in a particular layer is selected to provide an amount of oxygen and water-soluble molecule solubility such that oxygen and water-soluble molecule transport through the layer is optimized according to the desired function of that particular layer. Furthermore, in some embodiments, the ratio of silicone polymer to hydrophilic polymer as well as the polymeric compositions are selected such that a layer constructed from the material has interference characteristics that inhibit transport of one or more interfering species through the layer. Some known interfering species for a glucose sensor include, but are not limited to, acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid. Accordingly, in some embodiments, a silicone polymer/hydrophilic polymer layer as disclosed herein is less permeable to one or more of these interfering species than to the analyte, e.g., glucose.
- In some embodiments, silicone polymer/hydrophilic polymer blends are used in multiple layers of a membrane. In some of these embodiments, the ratio of silicone polymer to hydrophilic polymer in the layers incorporating the blends varies according to the desired functionality of each layer. The relative amounts of silicone polymer and hydrophilic polymer described below are based on the respective amounts found in the cured polymeric blend. Upon introduction into an aqueous environment, some of the polymeric components may leach out, thereby changing the relative amounts of silicone polymer and hydrophilic polymer. For example, significant amounts of the portions of the hydrophilic polymer that are not cross-linked may leach out.
- In some embodiments, the amount of any cross-linking between the silicone polymer and the hydrophilic polymer is substantially limited. In various embodiments, at least about 75%, 85%, 95%, or 99% of the silicone polymer is not covalently linked to the hydrophilic polymer. In some embodiments, the silicone polymer and the hydrophilic polymer do not cross link at all unless a cross-linking agent is used (e.g., such as described below). Similarly, in some embodiments, the amount of any entanglement (e.g., blending on a molecular level) between the silicone polymer and the hydrophilic polymer is substantially limited. In one embodiment, the silicone polymer and hydrophilic polymers form microdomains. For example, in one embodiment, the silicone polymer forms micellar structures surrounded by a network of hydrophilic polymer.
- The silicone polymer for use in the silicone/hydrophilic polymer blend may be any suitable silicone polymer. In some embodiments, the silicone polymer is a liquid silicone rubber that may be vulcanized using a metal- (e.g., platinum), peroxide-, heat-, ultraviolet-, or other radiation-catalyzed process. In some embodiments, the silicone polymer is a dimethyl- and methylhydrogen-siloxane copolymer. In some embodiments, the copolymer has vinyl substituents. In some embodiments, commercially available silicone polymers may be used. For example, commercially available silicone polymer precursor compositions may be used to prepare the blends, such as described below. In one embodiment, MED-4840 available from NUSIL® Technology LLC is used as a precursor to the silicone polymer used in the blend. MED-4840 consists of a 2-part silicone elastomer precursor including vinyl-functionalized dimethyl- and methylhydrogen-siloxane copolymers, amorphous silica, a platinum catalyst, a crosslinker, and an inhibitor. The two components may be mixed together and heated to initiate vulcanization, thereby forming an elastomeric solid material. Other suitable silicone polymer precursor systems include, but are not limited to, MED-2174 peroxide-cured liquid silicone rubber available from NUSIL® Technology LLC, SILASTIC® MDX4-4210 platinum-cured biomedical grade elastomer available from DOW CORNING®, and Implant Grade Liquid Silicone Polymer (durometers 10-50) available from Applied Silicone Corporation.
- The hydrophilic polymer for use in the blend may be any suitable hydrophilic polymer, including but not limited to components such as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate, polyvinylalcohol, polyacrylic acid, polyethers such as polyethylene glycol or polypropylene oxide, and copolymers thereof, including, for example, di-block, tri-block, alternating, random, comb, star, dendritic, and graft copolymers (block copolymers are discussed in U.S. Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein by reference). In one embodiment, the hydrophilic polymer is a copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). Suitable such polymers include, but are not limited to, PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating block copolymers of PEO-PPO, random copolymers of ethylene oxide and propylene oxide, and blends thereof. In some embodiments, the copolymers may be optionally substituted with hydroxy substituents. Commercially available examples of PEO and PPO copolymers include the PLURONIC® brand of polymers available from BASF®. Some PLURONIC® polymers are triblock copolymers of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) having the general molecular structure:
-
HO—(CH2CH2O)x—(CH2CH2CH2O)y—(CH2CH2O)x—OH - where the repeat units x and y vary among various PLURONIC® products. The poly(ethylene oxide) blocks act as a hydrophilic domain allowing the dissolution of aqueous agents in the polymer. The poly(propylene oxide) block acts as a hydrophobic domain facilitating the blending of the PLURONIC® polymer with a silicone polymer. In one embodiment, PLURONIC® F-127 is used having x of approximately 100 and y of approximately 65. The molecular weight of PLURONIC® F-127 is approximately 12,600 g/mol as reported by the manufacture. Other PLURONIC® polymers include PPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products). Other suitable commercial polymers include, but are not limited to, SYNPERONICS® products available from UNIQEMA®.
- The polyether structure of PLURONIC® polymers is relatively inert. Accordingly, without being bound by any particular theory, it is believed that the PLURONIC® polymers do not substantially react with the components in MED-4840 or other silicone polymer precursors.
- Those of skill in the art will appreciate that other copolymers having hydrophilic and hydrophobic domains may be used. For example, in one alternative embodiment, a triblock copolymer having the structure hydrophobic-hydrophilic-hydrophobic may be used. In another alternative embodiment, a diblock copolymer having the structure hydrophilic-hydrophobic is used.
- Layers that include a silicone polymer-hydrophilic polymer blend may be made using any of the methods of forming polymer blends known in the art. In one embodiment, a silicone polymer precursor (e.g., MED-4840) is mixed with a solution of a hydrophilic polymer (e.g., PLURONIC® F-127 dissolved in a suitable solvent such as acetone, ethyl alcohol, or 2-butanone). The mixture may then be drawn into a film or applied in a multi-layer membrane structure using any method known in the art (e.g., spraying, painting, dip coating, vapor depositing, molding, 3-D printing, lithographic techniques (e.g., photolithograph), micro- and nano-pipetting printing techniques, etc.). The mixture may then be cured under high temperature (e.g., 50-150° C.). Other suitable curing methods include ultraviolet or gamma radiation, for example. During curing, the silicone polymer precursor will vulcanize and the solvent will evaporate. In one embodiment, after the mixture is drawn into a film, another preformed layer of the membrane system is placed on the film. Curing of the film then provides bonding between the film and the other preformed layer. In one embodiment, the preformed layer is the cell disruptive layer. In one embodiment, the cell disruptive layer comprises a preformed porous silicone membrane. In other embodiments, the cell disruptive layer is also formed from a silicone polymer/hydrophilic polymer blend. In some embodiments, multiple films are applied on top of the preformed layer. Each film may posses a finite interface with adjacent films or may together form a physically continuous structure having a gradient in chemical composition.
- Some amount of cross-linking agent may also be included in the mixture to induce cross-linking between hydrophilic polymer molecules. For example, when using a PLURONIC® polymer, a cross-linking system that reacts with pendant or terminal hydroxy groups or methylene, ethylene, or propylene hydrogen atoms may be used to induce cross linking. Non-limiting examples of suitable cross-linking agents include ethylene glycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or dicumyl peroxide (DCP). While not being bound by any particular theory, at low concentrations, these cross-linking agents are believed to react primarily with the PLURONIC® polymer with some amount possibly inducing cross-linking in the silicone polymer or between the PLURONIC® polymer and the silicone polymer. In one embodiment, enough cross-linking agent is added such that the ratio of cross-linking agent molecules to hydrophilic polymer molecules added when synthesizing the blend is about 10 to about 30 (e.g., about 15 to about 20). In one embodiment, from about 0.5% to about 15% w/w of cross-linking agent is added relative to the total dry weights of cross-linking agent, silicone polymer, and hydrophilic polymer added when blending the ingredients (in one example, about 1% to about 10%). In one embodiment, from about 5% to about 30% of the dry ingredient weight is the PLURONIC® polymer. During the curing process, substantially all of the cross-linking agent is believed to react, leaving substantially no detectable unreacted cross-linking agent in the final film.
- In some embodiments, other agents may be added to the mixture to facilitate formation of the blend. For example, a small amount of butylhydroxy toluene (BHT) (e.g., about 0.01% w/w) or other suitable antioxidant may be mixed with a PLURONIC® to stabilize it.
- In some alternative embodiments, precursors of both the silicone polymer and hydrophilic polymer may be mixed prior to curing such that polymerization of both the silicone polymer and the hydrophilic polymer occur during curing. In another embodiment, already polymerized silicone polymer is mixed with a hydrophilic polymer such that no significant polymerization occurs during curing.
- The cell
disruptive layer 40 is positioned most distal to the implantable device and is designed to support tissue ingrowth, to disrupt contractile forces typically found in a foreign body capsule, to encourage vascularity within the membrane, and/or to disrupt the formation of a barrier cell layer. In one embodiment, the celldisruptive layer 40 has an open-celled configuration with interconnected cavities and solid portions, wherein the distribution of the solid portion and cavities of the cell disruptive layer includes a substantially co-continuous solid domain and includes more than one cavity in three dimensions substantially throughout the entirety of the first domain. Cells can enter into the cavities; however they cannot travel through or wholly exist within the solid portions. The cavities allow most substances to pass through, including, for example, cells, and molecules. U.S. Pat. No. 6,702,857, filed Jul. 27, 2001, and entitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES” and U.S. patent application Ser. No. 10/647,065, filed Aug. 22, 2003, published in U.S. Publication No. 2005/0112169 A1 and entitled, “POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES” describe membranes having a cell disruptive domain and are both incorporated herein by reference in their entirety. - The cell
disruptive layer 40 is preferably formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like. In these embodiments, transport of water-soluble agents such as an aqueous analyte occurs primarily through the pores and cavities of the layer. In some embodiments, the cell disruptive domain is formed from polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers, terpolymers of polytetrafluoroethylene, polyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), polyurethanes, cellulosic polymers, polysulfones or block copolymers thereof including, for example, di-block, tri-block, alternating, random and graft copolymers. In other embodiments, the cell disruptive layer is formed from a silicone composition with a non-silicon containing hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, or carbonates covalently incorporated or grafted therein such that water-soluble agents can also be transported through polymeric matrix of the celldisruptive layer 40. Such compositions are described for example in U.S. application Ser. No. 10/695,636, filed Oct. 28, 2003, published in Publication No. 2005/0090607 and entitled “SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE,” which is incorporated herein by reference in its entirety. In still other embodiments, the cell disruptive layer is formed from a monomer, polymer, copolymer, or blend including one or more of: lactic acid, glycolic acid, anhydrides, phospazenes, vinyl alcohol, ethylene vinyl alcohol, acetates, ε-caprolactone, β-hydroxybutyrate, γ-ethyl glutamate, DTH iminocarbonate, Bisphenol A iminocarbonate, sebacic acid, hexadecanoic acid, saccharides, chitosan, hydyoxyethyl methacrylate (HEMA), ceramics, hyaluronic acid (HA), collagen, gelatin, starches, hydroxy apatite, calcium phosphates, bioglasses, amino acid sequences, proteins, glycoproteins, protein fragments, agarose, fibrin, n-butylene, isobutylene, dioxanone, nylons, vinyl chlorides, amides, ethylenes, n-butyl methacrylate (BMA), metal matrix composites (MMCs), metal oxides (e.g. aluminum), DETOSU-1,6 HD-t-CDM ortho ester, styrene, and plasma treated surfaces of any of the above. - In some embodiments, the cell
disruptive layer 40 is formed from silicone polymer/hydrophilic polymer blends such as described above. Due to the open-cell configuration of the celldisruptive layer 40, the ratio of silicone polymer to hydrophilic polymer may be chosen to increase the structural integrity of the layer so that the open-cell configuration is maintained. Alternatively, the structural integrity of the cell disruptive layer can be increased by choosing a silicone polymer having properties suitable for increasing structural integrity (e.g., a silicone polymer having an increased durometer). In one embodiment, the concentration of hydrophilic polymer (e.g., PLURONIC® F-127) relative to silicone polymer (e.g., MED-4840) is from about 1% to about 30%, preferably from about 5% to about 20% in the celldisruptive layer 40. - In preferred embodiments, the thickness of the cell disruptive domain is from about 10 or less, 20, 30, 40, 50, 60, 70, 80, or 90 microns to about 1500, 2000, 2500, or 3000 or more microns. In more preferred embodiments, the thickness of the cell disruptive domain is from about 100, 150, 200 or 250 microns to about 1000, 1100, 1200, 1300, or 1400 microns. In even more preferred embodiments, the thickness of the cell disruptive domain is from about 300, 350, 400, 450, 500, or 550 microns to about 500, 550, 600, 650, 700, 750, 800, 850, or 900 microns.
- The cell disruptive domain is optional and can be omitted when using an implantable device that does not prefer tissue ingrowth, for example, a short-lived device (for example, less than one day to about a week or up to about one month) or one that delivers tissue response modifiers.
- The
bioprotective layer 42 is positioned less distal to the implantable device than the cell disruptive layer, and can be resistant to cellular attachment, impermeable to cells, and/or is composed of a biostable material. When the bioprotective layer is resistant to cellular attachment (for example, attachment by inflammatory cells, such as macrophages, which are therefore kept a sufficient distance from other domains, for example, the enzyme domain), hypochlorite and other oxidizing species are short-lived chemical species in vivo, and biodegradation does not occur. Additionally, the materials preferred for forming thebioprotective layer 42 may be resistant to the effects of these oxidative species and have thus been termed biodurable. See, for example, U.S. Pat. No. 6,702,857, filed Jul. 27, 2001, and entitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES” and U.S. patent application Ser. No. 10/647,065, filed Aug. 22, 2003, published in Publication No. 20050112169 and entitled, “POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES,” both of which are incorporated herein by reference in their entirety. - In one embodiment,
bioprotective layer 42 is formed from high oxygen soluble materials such as polymers formed from silicone, fluorocarbons, perfluorocarbons, or the like. In one embodiment, the cell impermeable domain is formed from a silicone composition with a hydrophile such as such as polyethylene glycol, propylene glycol, pyrrolidone, esters, amides, carbonates, or polypropylene glycol covalently incorporated or grafted therein. In still other embodiments, the bioprotective layer is formed from a monomer, polymer, copolymer, or blend including one or more of: lactic acid, glycolic acid, anhydrides, phospazenes, vinyl alcohol, ethylene vinyl alcohol, acetates, ε-caprolactone, β-hydroxybutyrate, γ-ethyl glutamate, DTH iminocarbonate, Bisphenol A iminocarbonate, sebacic acid, hexadecanoic acid, saccharides, chitosan, hydyoxyethyl methacrylate (HEMA), ceramics, hyaluronic acid (HA), collagen, gelatin, starches, hydroxy apatite, calcium phosphates, bioglasses, amino acid sequences, proteins, glycoproteins, protein fragments, agarose, fibrin, n-butylene, isobutylene, dioxanone, nylons, vinyl chlorides, amides, ethylenes, n-butyl methacrylate (BMA), metal matrix composites (MMCs), metal oxides (e.g. aluminum), DETOSU-1,6 HD-t-CDM ortho ester, styrene, and plasma treated surfaces of any of the above. - In one preferred embodiment, the
bioprotective layer 42 is formed from silicone polymer/hydrophilic polymer blends such as described above. It is advantageous that the cellimpermeable layer 42 have both high oxygen and aqueous analyte solubility so that sufficient reactants reach the enzyme layer. Accordingly, in one embodiment, the concentration of hydrophilic polymer (e.g., PLURONIC® F-127) relative to silicone polymer (e.g., MED-4840) is relatively high, e.g., from about 10% to about 30% in thebioprotective layer 42. In one embodiment, the concentration of hydrophilic polymer is from about 15% to about 25% (e.g., about 20%). - In preferred embodiments, the thickness of the bioprotective layer is from about 10 or 15 microns or less to about 125, 150, 175, 200 or 250 microns or more. In more preferred embodiments, the thickness of the bioprotective layer is from about 20, 25, 30, or 35 microns to about 60, 65, 70, 75, 80, 85, 90, 95, or 100 microns. In even more preferred embodiments, the bioprotective layer is from about 20 or 25 microns to about 50, 55, or 60 microns thick.
- The cell
disruptive layer 40 andbioprotective layer 42 of the membrane system can be formed together as one unitary structure. Alternatively, the cell disruptive andbioprotective layers disruptive layer 40 andbioprotective layer 42 consist of a unitary structure having graduated properties. For example, the porosity of the unitary structure may vary from high porosity at the tissue side of the layer to very low or no porosity at the sensor side. In addition, the chemical properties of such a graduated structure may also vary. For example, the concentration of the hydrophilic polymer may vary throughout the structure, increasing in concentration toward the sensor side of the layer. The lower concentration on the tissue side allows for increased structural integrity to support an open-celled structure while the higher concentration on the sensor side promotes increased transport of aqueous analytes through the polymer blend. - The
diffusion resistance layer - The
diffusion resistance layer underlying enzyme layer diffusion resistance layer - In one embodiment, the
diffusion resistance layer - In some preferred embodiments, the
diffusion resistance layer diffusion resistance layer - In some alternative embodiments, the diffusion resistance layer includes a polyurethane membrane with both hydrophilic and hydrophobic regions to control the diffusion of glucose and oxygen to an analyte sensor, the membrane being fabricated easily and reproducibly from commercially available materials. A suitable hydrophobic polymer component is a polyurethane, or polyetherurethaneurea. Polyurethane is a polymer produced by the condensation reaction of a diisocyanate and a difunctional hydroxyl-containing material. A polyurethaneurea is a polymer produced by the condensation reaction of a diisocyanate and a difunctional amine-containing material. Preferred diisocyanates include aliphatic diisocyanates containing from about 4 to about 8 methylene units. Diisocyanates containing cycloaliphatic moieties can also be useful in the preparation of the polymer and copolymer components of the membranes of preferred embodiments. The material that forms the basis of the hydrophobic matrix of the diffusion resistance layer can be any of those known in the art as appropriate for use as membranes in sensor devices and as having sufficient permeability to allow relevant compounds to pass through it, for example, to allow an oxygen molecule to pass through the membrane from the sample under examination in order to reach the active enzyme or electrochemical electrodes. Examples of materials which can be used to make non-polyurethane type membranes include vinyl polymers, polyethers, polyesters, polyamides, inorganic polymers such as polysiloxanes and polycarbosiloxanes, natural polymers such as cellulosic and protein based materials, and mixtures or combinations thereof.
- In one embodiment, the hydrophilic polymer component is polyethylene oxide. For example, one useful hydrophilic copolymer component is a polyurethane polymer that includes about 20% hydrophilic polyethylene oxide. The polyethylene oxide portions of the copolymer are thermodynamically driven to separate from the hydrophobic portions of the copolymer and the hydrophobic polymer component. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the water pick-up and subsequent glucose permeability of the membrane.
- In some embodiments, the
diffusion resistance layer bioprotective layer 42; that is, the inherent properties of thediffusion resistance layer bioprotective layer 42 such that thebioprotective layer 42 is incorporated as a part ofdiffusion resistance layer disruptive layer 40. As discussed above, the diffusion resistance layer/bioprotective layer may also be part of a unitary structure with the celldisruptive layer 40 such that the outer layer of the membrane system is graduated to the interface with the enzyme layer. In another embodiment, the diffusion resistance layer/bioprotective layer may also be part of a unitary structure with the celldisruptive layer 40 including a chemical gradient with transition properties between the outer layer and the enzyme layer. In another embodiment, thediffusion resistance layer - In still another embodiment, the diffusion resistance layer may be a distinct layer from the cell disruptive layer or the bioprotective layer but may nonetheless include a chemical gradient such that its diffusion resistance property transitions from one side of the layer to the other. Similarly, the cell disruptive layer and bioprotective layers may also include a chemical gradient. Where multiple such layers have chemical gradients, the chemical compositions at the interface between two layers may be identical or different.
- In preferred embodiments, the thickness of the resistance domain is from about 0.05 microns or less to about 200 microns or more. In more preferred embodiments, the thickness of the resistance domain is from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 10, 15, 20, 25, 30, or 35 microns to about, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, or 100 microns. In more preferred embodiments, the thickness of the resistance domain is from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case of a transcutaneously implanted sensor or from about 20 or 25 microns to about 40 or 50 microns in the case of a wholly implanted sensor.
- An immobilized
enzyme layer diffusion resistance layer enzyme layer enzyme layer - The
enzyme layer enzyme layer - In one embodiment, high oxygen solubility within the enzyme layer can be achieved by using a polymer matrix to host the enzyme within the enzyme layer that has a high solubility of oxygen. In one exemplary embodiment of fluorocarbon-based polymers, the solubility of oxygen within a perfluorocarbon-based polymer is 50-volume %. As a reference, the solubility of oxygen in water is approximately 2-volume %.
- In one preferred embodiment, the enzyme layer is formed from silicone polymer/hydrophilic polymer blends such as described above. In one embodiment, the concentration of hydrophilic polymer (e.g., PLURONIC® F-127) relative to silicone polymer (e.g., MED-4840) is relatively high, e.g., from about 10% to about 30% in the
bioprotective layer 42. In one embodiment, the concentration of hydrophilic polymer is from about 15% to about 25% (e.g., about 20%). - Utilization of a high oxygen solubility material for the enzyme layer is advantageous because the oxygen dissolves more readily within the layer and thereby acts as a high oxygen soluble domain optimizing oxygen availability to oxygen-utilizing sources (for example, the enzyme and/or counter electrode). When the
diffusion resistance layer enzyme layer enzyme layer diffusion resistance layer - In some alternative embodiments, the enzyme domain is constructed of aqueous dispersions of colloidal polyurethane polymers including the enzyme.
- In preferred embodiments, the thickness of the enzyme domain is from about 0.05 micron or less to about 20, 30 40, 50, 60, 70, 80, 90, or 100 microns or more. In more preferred embodiments, the thickness of the enzyme domain is between about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 microns and 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 25, or 30 microns. In even more preferred embodiments, the thickness of the enzyme domain is from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case of a transcutaneously implanted sensor or from about 6, 7, or 8 microns to about 9, 10, 11, or 12 microns in the case of a wholly implanted sensor.
- The
interference layer interference layer - In one embodiment, the
interference domain interference layer - In another embodiment, the
interference layer interference layer interference layer - In one embodiment, the
interference layer - In some embodiments, the
interference layer - In one preferred embodiment, the
interference layer - In one alternative embodiment, the
interference layer - Layer(s) prepared from combinations of cellulose acetate and cellulose acetate butyrate, or combinations of layer(s) of cellulose acetate and layer(s) of cellulose acetate butyrate can also be employed to form the
interference layer - In some alternative embodiments, additional polymers, such as Nafion®, can be used in combination with cellulosic derivatives to provide equivalent and/or enhanced function of the
interference layer - In some alternative embodiments, more than one cellulosic derivative can be used to form the
interference layer interference layer - In some alternative embodiments, other polymer types that can be utilized as a base material for the
interference layer interference layer - In preferred embodiments, the thickness of the interference domain is from about 0.05 microns or less to about 20 microns or more. In more preferred embodiments, the thickness of the interference domain is between about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns and about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns. In more preferred embodiments, the thickness of the interference domain is from about 0.6, 0.7, 0.8, 0.9, or 1 micron to about 2, 3, or 4 microns.
- An
electrode layer interference layer electrode layer electrode layer interference layer electrode layer - In one embodiment, the
electrode layer - In some embodiments, the
electrode layer electrode layer electrode layer - Underlying the electrode layer is an electrolyte phase is a free-fluid phase including a solution containing at least one compound, typically a soluble chloride salt, which conducts electric current. In one embodiment wherein the membrane system is used with a glucose sensor such as is described herein, the electrolyte phase flows over the electrodes and is in contact with the electrolyte layer. The devices of the preferred embodiments contemplate the use of any suitable electrolyte solution, including standard, commercially available solutions. Generally, the electrolyte phase can have the same osmotic pressure or a lower osmotic pressure than the sample being analyzed. In preferred embodiments, the electrolyte phase comprises normal saline.
- In various embodiments, any of the layers discussed above can be omitted, altered, substituted for, and/or incorporated together. For example, a distinct bioprotective layer may not exist. In such embodiments, other domains accomplish the function of the bioprotective layer. As another example, the interference layer can be eliminated in certain embodiments wherein two-electrode differential measurements are employed to eliminate interference, for example, one electrode being sensitive to glucose and electrooxidizable interferants and the other only to interferants, such as is described in U.S. Pat. No. 6,514,718, which is incorporated herein by reference in its entirety. In such embodiments, the interference layer can be omitted.
- In one embodiment, the
membrane system 18 comprises only two layers. One layer is the enzyme layer as described above. The second layer is positioned more distal than the enzyme layer and serves one or more of the functions described above for the cell disruptive layer, bioprotective layer, and diffusion resistance layer. In one embodiment, this second layer is graduated either structurally and/or chemically as describe above such that different domains of the second layer serve different functions such as cell disruption, bio-protection, or diffusion resistance. In one embodiment, both layers of this membrane system are formed from silicone polymer/hydrophilic polymer blends such as described above. - In one embodiment, every layer in the
membrane system 18 is formed from silicone polymer/hydrophilic polymer blends such as described above. Such uniformity in ingredients allows for ease of manufacturing while at the same time allowing for tailoring of properties by varying the ratio of silicone polymer to hydrophilic polymer. - 30 g of PLURONIC® F-127 (PF-127) was dissolved under stirring in 100 g of anhydrous acetone at 40° C. 13 g of acetone was added to 37.3 g of the PF-127 solution followed by adding 4.8 g of dicumyl peroxide (DCP). 40 g of MED-4840 was mixed in a speed mixer at a speed of 3300 rpm for 60 seconds. The MED-4840 mixture was then placed in a motorized mechanical mixer equipped with a spiral dough hook. The mixture was stirred at low speed for 30 s. The stirring speed was then increased to medium-low and the PF-127/DCP solution was added at a rate of 3.5-4.0 g every 30 seconds. After all of the PF-127/DCP solution was added, the mixture was stirred at medium speed for 3 minutes. The mixture was then placed in a Speed Mixer and mixed at 3300 rpm for 60 seconds. This process was repeated until the desired viscosity was reached.
- 5-10 mL of the mixture was placed in an evenly-distributed line between the arms of the drawdown blade on a drawdown machine. The drawdown machine was used to create a 9 inch long and 0.0045 inch thick film at a speed of about 0.7 inches/minute. A preformed piece of porous silicone (to act as a cell disruptive layer) was placed skin side down on the drawn film and tapped lightly to promote the polymeric mixture to penetrate into the pores of the porous silicone. The film was then cured for 1.5 hours at 100° C.
- A MED-4840/PLURONIC® F-127 membrane was manufactured using 8.4% PLURONIC® and 1.8% of a DCP cross-linking agent. This membrane was placed over a two-layer membrane having an enzyme layer and an electrode layer. The combined membrane layers were placed on a wholly implantable glucose sensor. The sensor was sterilized and implanted into a diabetic rat model.
FIG. 6 is a graph depicting the resulting glucose sensor measurements over the course of approximately two months. The small points inFIG. 6 depict glucose concentrations measured by the sensor and the large points depict glucose concentrations measured by separate blood glucose assays. The graph indicates a close correlation between the sensor glucose measurements and the blood glucose measurements. - A MED-4840/PLURONIC® F-127 membrane was manufactured using 20% PLURONIC® and a 20:1 ratio of DCP cross-linking agent per PLURONIC®. Prior to curing, the material was drawn down and a cell-disruptive porous silicone membrane was placed on the uncured layer. After curing, the combined bioprotective/porous silicone membrane was placed over a four-layer membrane having a diffusion resistance layer, enzyme layer, interference layer, and electrode layer. The combined membrane layers were placed on a wholly implantable glucose sensor. The sensor was sterilized and implanted into a diabetic rat model.
FIG. 7 is a graph depicting the resulting glucose sensor measurements over the course of approximately two months. The small points inFIG. 7 depict glucose concentrations measured by the sensor and the large points depict glucose concentrations measured by separate blood glucose assays. The graph indicates a close correlation between the sensor glucose measurements and the blood glucose measurements. - A MED-4840/PLURONIC® F-127 membrane was manufactured using 8.4% PLURONIC® and 3.7% DCP. This membrane was placed over two-layer membrane having an electrode layer and an enzyme layer. The combined membrane layers were installed on a wholly implantable glucose sensor. The sensor was placed into a 2 L bath filled with PBS (saline). The continuously stirred bath was brought to 37° C. and the sensor allowed to equilibrate for a minimum of 1 hour until the sensors reached a flat line continuous baseline signal. Acetaminophen was then added to the bath to a dilution of 3.8 mg/dl. The sensor was then allowed to equilibrate over 1 hour while measurements were continuously recorded from the sensor.
FIG. 8 is a graph show the sensor signal over the course of the hour. The graph indicates that the signal changed by less than 1%. Thus, the sensor was substantially insensitive to the presence of acetaminophen, indicating that the membrane substantially reduces transport of acetaminophen therethrough. - As a comparative example, a wholly implantable glucose sensor with a membrane not including a silicone/hydrophilic-hydrophobic polymer blend was tested. The membrane in this sensor included a three-layer membrane having an electrode layer, an enzyme layer, and a polyurethane diffusion resistance layer. A porous silicone cell disruptive layer was added on top. The sensor was placed into a 2 L bath filled with PBS (saline). The continuously stirred bath was brought to 37° C. and the sensor allowed to equilibrate for a minimum of 1 hour until the sensors reached a flat line continuous baseline signal. Acetaminophen was then added to the bath to a dilution of 3.8 mg/dl. The sensor was then allowed to equilibrate over 1 hour while measurements were continuously recorded from the sensor.
FIG. 9 is a graph show the sensor signal over the course of the hour. The graph indicates that the signal changed by more than 15% after introduction of the acetaminophen. Thus, without the silicone/hydrophilic-hydrophobic polymer blend sensor was sensitive to the acetaminophen interferant. - Methods and devices that are suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. Pat. Nos. 4,994,167; 4,757,022; 6,001,067; 6,741,877; 6,702,857; 6,558,321; 6,931,327; and 6,862,465.
- Methods and devices that are suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. Publication No. US-2005-0176136-A1; U.S. Publication No. US-2005-0251083-A1; U.S. Publication No. US-2005-0143635-A1; U.S. Publication No. US-2005-0181012-A1; U.S. Publication No. US-2005-0177036-A1; U.S. Publication No. US-2005-0124873-A1; U.S. Publication No. US-2005-0051440-A1; U.S. Publication No. US-2005-0115832-A1; U.S. Publication No. US-2005-0245799-A1; U.S. Publication No. US-2005-0245795-A1; U.S. Publication No. US-2005-0242479-A1; U.S. Publication No. US-2005-0182451-A1; U.S. Publication No. US-2005-0056552-A1; U.S. Publication No. US-2005-0192557-A1; U.S. Publication No. US-2005-0154271-A1; U.S. Publication No. US-2004-0199059-A1; U.S. Publication No. US-2005-0054909-A1; U.S. Publication No. US-2005-0112169-A1; U.S. Publication No. US-2005-0051427-A1; U.S. Publication No. US-2003-0032874; U.S. Publication No. US-2005-0103625-A1; U.S. Publication No. US-2005-0203360-A1; U.S. Publication No. US-2005-0090607-A1; U.S. Publication No. US-2005-0187720-A1; U.S. Publication No. US-2005-0161346-A1; U.S. Publication No. US-2006-0015020-A1; U.S. Publication No. US-2005-0043598-A1; U.S. Publication No. US-2003-0217966-A1; U.S. Publication No. US-2005-0033132-A1; U.S. Publication No. US-2005-0031689-A1; U.S. Publication No. US-2004-0045879-A1; U.S. Publication No. US-2004-0186362-A1; U.S. Publication No. US-2005-0027463-A1; U.S. Publication No. US-2005-0027181-A1; U.S. Publication No. US-2005-0027180-A1; U.S. Publication No. US-2006-0020187-A1; U.S. Publication No. US-2006-0036142-A1; U.S. Publication No. US-2006-0020192-A1; U.S. Publication No. US-2006-0036143-A1; U.S. Publication No. US-2006-0036140-A1; U.S. Publication No. US-2006-0019327-A1; U.S. Publication No. US-2006-0020186-A1; U.S. Publication No. US-2006-0020189-A1; U.S. Publication No. US-2006-0036139-A1; U.S. Publication No. US-2006-0020191-A1; U.S. Publication No. US-2006-0020188-A1; U.S. Publication No. US-2006-0036141-A1; U.S. Publication No. US-2006-0020190-A1; U.S. Publication No. US-2006-0036145-A1; U.S. Publication No. US-2006-0036144-A1; and U.S. Publication No. US-2006-0016700A1.
- Methods and devices that are suitable for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/280,672 filed Nov. 16, 2005, and entitled “TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No. 11/280,102 filed Nov. 16, 2005, and entitled “TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No. 11/201,445 filed Aug. 10, 2005 and entitled “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. application Ser. No. 11/335,879 filed Jan. 18, 2006 and entitled “CELLULOSIC-BASED INTERFERENCE DOMAIN FOR AN ANALYTE SENSOR”; U.S. application Ser. No. 11/334,876 filed Jan. 18, 2006 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. application Ser. No. 11/333,837 filed Jan. 17, 2006 and entitled “LOW OXYGEN IN VIVO ANALYTE SENSOR”.
- All references cited herein are incorporated herein by reference in their entireties. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
- The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
- All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
- The above description discloses several methods and materials of the present invention. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention as embodied in the attached claims.
Claims (3)
1-17. (canceled)
18. A system for measuring an analyte concentration in a host, the system comprising:
a transcutaneous analyte sensor; and
sensor electronics configured to operatively connect to the transcutaneous analyte sensor.
19. A method for processing data from a transcutaneous analyte sensor, the method comprising:
receiving sensor data indicative of an analyte concentration in the host; and
processing, using a processor, the sensor data.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230218210A1 (en) * | 2015-12-30 | 2023-07-13 | Dexcom, Inc. | Transcutaneous analyte sensor systems and methods |
US11857344B2 (en) | 2021-05-08 | 2024-01-02 | Biolinq Incorporated | Fault detection for microneedle array based continuous analyte monitoring device |
US11872055B2 (en) | 2020-07-29 | 2024-01-16 | Biolinq Incorporated | Continuous analyte monitoring system with microneedle array |
US11963796B1 (en) | 2017-04-29 | 2024-04-23 | Biolinq Incorporated | Heterogeneous integration of silicon-fabricated solid microneedle sensors and CMOS circuitry |
Families Citing this family (272)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5593852A (en) | 1993-12-02 | 1997-01-14 | Heller; Adam | Subcutaneous glucose electrode |
US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
US6134461A (en) | 1998-03-04 | 2000-10-17 | E. Heller & Company | Electrochemical analyte |
US9066695B2 (en) | 1998-04-30 | 2015-06-30 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8480580B2 (en) | 1998-04-30 | 2013-07-09 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8465425B2 (en) | 1998-04-30 | 2013-06-18 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6175752B1 (en) | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
US8688188B2 (en) | 1998-04-30 | 2014-04-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6949816B2 (en) | 2003-04-21 | 2005-09-27 | Motorola, Inc. | Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same |
US8346337B2 (en) | 1998-04-30 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
US6932894B2 (en) * | 2001-05-15 | 2005-08-23 | Therasense, Inc. | Biosensor membranes composed of polymers containing heterocyclic nitrogens |
US20030032874A1 (en) | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
US8364229B2 (en) | 2003-07-25 | 2013-01-29 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US7828728B2 (en) | 2003-07-25 | 2010-11-09 | Dexcom, Inc. | Analyte sensor |
US7613491B2 (en) | 2002-05-22 | 2009-11-03 | Dexcom, Inc. | Silicone based membranes for use in implantable glucose sensors |
US7727181B2 (en) | 2002-10-09 | 2010-06-01 | Abbott Diabetes Care Inc. | Fluid delivery device with autocalibration |
US7993108B2 (en) | 2002-10-09 | 2011-08-09 | Abbott Diabetes Care Inc. | Variable volume, shape memory actuated insulin dispensing pump |
CA2501825C (en) | 2002-10-09 | 2009-12-01 | Therasense, Inc. | Fluid delivery device, system and method |
US9237865B2 (en) * | 2002-10-18 | 2016-01-19 | Medtronic Minimed, Inc. | Analyte sensors and methods for making and using them |
US7381184B2 (en) | 2002-11-05 | 2008-06-03 | Abbott Diabetes Care Inc. | Sensor inserter assembly |
AU2003303597A1 (en) | 2002-12-31 | 2004-07-29 | Therasense, Inc. | Continuous glucose monitoring system and methods of use |
US7587287B2 (en) | 2003-04-04 | 2009-09-08 | Abbott Diabetes Care Inc. | Method and system for transferring analyte test data |
US7679407B2 (en) | 2003-04-28 | 2010-03-16 | Abbott Diabetes Care Inc. | Method and apparatus for providing peak detection circuitry for data communication systems |
US8460243B2 (en) | 2003-06-10 | 2013-06-11 | Abbott Diabetes Care Inc. | Glucose measuring module and insulin pump combination |
US8066639B2 (en) | 2003-06-10 | 2011-11-29 | Abbott Diabetes Care Inc. | Glucose measuring device for use in personal area network |
US8071028B2 (en) | 2003-06-12 | 2011-12-06 | Abbott Diabetes Care Inc. | Method and apparatus for providing power management in data communication systems |
US7722536B2 (en) | 2003-07-15 | 2010-05-25 | Abbott Diabetes Care Inc. | Glucose measuring device integrated into a holster for a personal area network device |
US9763609B2 (en) | 2003-07-25 | 2017-09-19 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
EP1648298A4 (en) | 2003-07-25 | 2010-01-13 | Dexcom Inc | Oxygen enhancing membrane systems for implantable devices |
US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
US7299082B2 (en) | 2003-10-31 | 2007-11-20 | Abbott Diabetes Care, Inc. | Method of calibrating an analyte-measurement device, and associated methods, devices and systems |
USD914881S1 (en) | 2003-11-05 | 2021-03-30 | Abbott Diabetes Care Inc. | Analyte sensor electronic mount |
US8774886B2 (en) | 2006-10-04 | 2014-07-08 | Dexcom, Inc. | Analyte sensor |
WO2005089103A2 (en) | 2004-02-17 | 2005-09-29 | Therasense, Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
US8277713B2 (en) | 2004-05-03 | 2012-10-02 | Dexcom, Inc. | Implantable analyte sensor |
CA2572455C (en) | 2004-06-04 | 2014-10-28 | Therasense, Inc. | Diabetes care host-client architecture and data management system |
US7654956B2 (en) | 2004-07-13 | 2010-02-02 | Dexcom, Inc. | Transcutaneous analyte sensor |
US9398882B2 (en) | 2005-09-30 | 2016-07-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor and data processing device |
US9743862B2 (en) | 2011-03-31 | 2017-08-29 | Abbott Diabetes Care Inc. | Systems and methods for transcutaneously implanting medical devices |
US8333714B2 (en) | 2006-09-10 | 2012-12-18 | Abbott Diabetes Care Inc. | Method and system for providing an integrated analyte sensor insertion device and data processing unit |
US9572534B2 (en) | 2010-06-29 | 2017-02-21 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
US10226207B2 (en) | 2004-12-29 | 2019-03-12 | Abbott Diabetes Care Inc. | Sensor inserter having introducer |
US7697967B2 (en) | 2005-12-28 | 2010-04-13 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
US7731657B2 (en) | 2005-08-30 | 2010-06-08 | Abbott Diabetes Care Inc. | Analyte sensor introducer and methods of use |
US9636450B2 (en) | 2007-02-19 | 2017-05-02 | Udo Hoss | Pump system modular components for delivering medication and analyte sensing at seperate insertion sites |
US8571624B2 (en) | 2004-12-29 | 2013-10-29 | Abbott Diabetes Care Inc. | Method and apparatus for mounting a data transmission device in a communication system |
US9788771B2 (en) | 2006-10-23 | 2017-10-17 | Abbott Diabetes Care Inc. | Variable speed sensor insertion devices and methods of use |
US8512243B2 (en) | 2005-09-30 | 2013-08-20 | Abbott Diabetes Care Inc. | Integrated introducer and transmitter assembly and methods of use |
US20090105569A1 (en) | 2006-04-28 | 2009-04-23 | Abbott Diabetes Care, Inc. | Introducer Assembly and Methods of Use |
US9259175B2 (en) | 2006-10-23 | 2016-02-16 | Abbott Diabetes Care, Inc. | Flexible patch for fluid delivery and monitoring body analytes |
US7883464B2 (en) | 2005-09-30 | 2011-02-08 | Abbott Diabetes Care Inc. | Integrated transmitter unit and sensor introducer mechanism and methods of use |
US9351669B2 (en) | 2009-09-30 | 2016-05-31 | Abbott Diabetes Care Inc. | Interconnect for on-body analyte monitoring device |
US8029441B2 (en) | 2006-02-28 | 2011-10-04 | Abbott Diabetes Care Inc. | Analyte sensor transmitter unit configuration for a data monitoring and management system |
US7545272B2 (en) | 2005-02-08 | 2009-06-09 | Therasense, Inc. | RF tag on test strips, test strip vials and boxes |
BRPI0609511A2 (en) | 2005-03-21 | 2010-04-13 | Abbott Diabetes Care Inc | system including an infusion device and an analyte monitoring unit, method for integrating analyte monitoring and fluid infusion, apparatus including an analyte sensor and a fluid supply channel, and a fluid supply method and analyte monitoring |
US8744546B2 (en) | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
US8112240B2 (en) | 2005-04-29 | 2012-02-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing leak detection in data monitoring and management systems |
US7768408B2 (en) | 2005-05-17 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing data management in data monitoring system |
US7620437B2 (en) | 2005-06-03 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and apparatus for providing rechargeable power in data monitoring and management systems |
US20080314395A1 (en) | 2005-08-31 | 2008-12-25 | Theuniversity Of Virginia Patent Foundation | Accuracy of Continuous Glucose Sensors |
US9521968B2 (en) | 2005-09-30 | 2016-12-20 | Abbott Diabetes Care Inc. | Analyte sensor retention mechanism and methods of use |
US8880138B2 (en) | 2005-09-30 | 2014-11-04 | Abbott Diabetes Care Inc. | Device for channeling fluid and methods of use |
US7756561B2 (en) | 2005-09-30 | 2010-07-13 | Abbott Diabetes Care Inc. | Method and apparatus for providing rechargeable power in data monitoring and management systems |
US7583190B2 (en) | 2005-10-31 | 2009-09-01 | Abbott Diabetes Care Inc. | Method and apparatus for providing data communication in data monitoring and management systems |
US7766829B2 (en) | 2005-11-04 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing basal profile modification in analyte monitoring and management systems |
US11298058B2 (en) | 2005-12-28 | 2022-04-12 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
EP1968432A4 (en) | 2005-12-28 | 2009-10-21 | Abbott Diabetes Care Inc | Medical device insertion |
US7736310B2 (en) | 2006-01-30 | 2010-06-15 | Abbott Diabetes Care Inc. | On-body medical device securement |
US8344966B2 (en) | 2006-01-31 | 2013-01-01 | Abbott Diabetes Care Inc. | Method and system for providing a fault tolerant display unit in an electronic device |
US7981034B2 (en) | 2006-02-28 | 2011-07-19 | Abbott Diabetes Care Inc. | Smart messages and alerts for an infusion delivery and management system |
US7885698B2 (en) | 2006-02-28 | 2011-02-08 | Abbott Diabetes Care Inc. | Method and system for providing continuous calibration of implantable analyte sensors |
US7826879B2 (en) | 2006-02-28 | 2010-11-02 | Abbott Diabetes Care Inc. | Analyte sensors and methods of use |
US8478557B2 (en) | 2009-07-31 | 2013-07-02 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte monitoring system calibration accuracy |
US8140312B2 (en) | 2007-05-14 | 2012-03-20 | Abbott Diabetes Care Inc. | Method and system for determining analyte levels |
US8374668B1 (en) | 2007-10-23 | 2013-02-12 | Abbott Diabetes Care Inc. | Analyte sensor with lag compensation |
US7653425B2 (en) | 2006-08-09 | 2010-01-26 | Abbott Diabetes Care Inc. | Method and system for providing calibration of an analyte sensor in an analyte monitoring system |
US7630748B2 (en) | 2006-10-25 | 2009-12-08 | Abbott Diabetes Care Inc. | Method and system for providing analyte monitoring |
US8219173B2 (en) | 2008-09-30 | 2012-07-10 | Abbott Diabetes Care Inc. | Optimizing analyte sensor calibration |
US8473022B2 (en) | 2008-01-31 | 2013-06-25 | Abbott Diabetes Care Inc. | Analyte sensor with time lag compensation |
US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
US9326709B2 (en) | 2010-03-10 | 2016-05-03 | Abbott Diabetes Care Inc. | Systems, devices and methods for managing glucose levels |
US7618369B2 (en) | 2006-10-02 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for dynamically updating calibration parameters for an analyte sensor |
US7801582B2 (en) | 2006-03-31 | 2010-09-21 | Abbott Diabetes Care Inc. | Analyte monitoring and management system and methods therefor |
US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
US9339217B2 (en) | 2011-11-25 | 2016-05-17 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods of use |
US9675290B2 (en) | 2012-10-30 | 2017-06-13 | Abbott Diabetes Care Inc. | Sensitivity calibration of in vivo sensors used to measure analyte concentration |
US8346335B2 (en) | 2008-03-28 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte sensor calibration management |
US9392969B2 (en) | 2008-08-31 | 2016-07-19 | Abbott Diabetes Care Inc. | Closed loop control and signal attenuation detection |
US8224415B2 (en) | 2009-01-29 | 2012-07-17 | Abbott Diabetes Care Inc. | Method and device for providing offset model based calibration for analyte sensor |
US20080064937A1 (en) | 2006-06-07 | 2008-03-13 | Abbott Diabetes Care, Inc. | Analyte monitoring system and method |
US9119582B2 (en) | 2006-06-30 | 2015-09-01 | Abbott Diabetes Care, Inc. | Integrated analyte sensor and infusion device and methods therefor |
US8932216B2 (en) | 2006-08-07 | 2015-01-13 | Abbott Diabetes Care Inc. | Method and system for providing data management in integrated analyte monitoring and infusion system |
US8206296B2 (en) | 2006-08-07 | 2012-06-26 | Abbott Diabetes Care Inc. | Method and system for providing integrated analyte monitoring and infusion system therapy management |
BRPI0718119A2 (en) | 2006-10-26 | 2014-07-08 | Abbott Diabetes Care Inc | COMPUTER METHODS, SYSTEMS, AND PROGRAMS FOR REAL-TIME DETECTION OF THE ANALYTIC SENSOR SENSITIVITY DECLINE |
US8579853B2 (en) | 2006-10-31 | 2013-11-12 | Abbott Diabetes Care Inc. | Infusion devices and methods |
US8121857B2 (en) | 2007-02-15 | 2012-02-21 | Abbott Diabetes Care Inc. | Device and method for automatic data acquisition and/or detection |
US20080199894A1 (en) | 2007-02-15 | 2008-08-21 | Abbott Diabetes Care, Inc. | Device and method for automatic data acquisition and/or detection |
US8732188B2 (en) | 2007-02-18 | 2014-05-20 | Abbott Diabetes Care Inc. | Method and system for providing contextual based medication dosage determination |
US8930203B2 (en) | 2007-02-18 | 2015-01-06 | Abbott Diabetes Care Inc. | Multi-function analyte test device and methods therefor |
US8123686B2 (en) | 2007-03-01 | 2012-02-28 | Abbott Diabetes Care Inc. | Method and apparatus for providing rolling data in communication systems |
EP2796093A1 (en) | 2007-03-26 | 2014-10-29 | DexCom, Inc. | Analyte sensor |
ES2784736T3 (en) | 2007-04-14 | 2020-09-30 | Abbott Diabetes Care Inc | Procedure and apparatus for providing data processing and control in a medical communication system |
WO2008130896A1 (en) | 2007-04-14 | 2008-10-30 | Abbott Diabetes Care, Inc. | Method and apparatus for providing data processing and control in medical communication system |
US9008743B2 (en) | 2007-04-14 | 2015-04-14 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
EP2146622B1 (en) | 2007-04-14 | 2016-05-11 | Abbott Diabetes Care Inc. | Method and apparatus for providing dynamic multi-stage signal amplification in a medical device |
WO2009096992A1 (en) | 2007-04-14 | 2009-08-06 | Abbott Diabetes Care, Inc. | Method and apparatus for providing data processing and control in medical communication system |
CA2683930A1 (en) | 2007-04-14 | 2008-10-23 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
US8456301B2 (en) | 2007-05-08 | 2013-06-04 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US7928850B2 (en) | 2007-05-08 | 2011-04-19 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US8665091B2 (en) | 2007-05-08 | 2014-03-04 | Abbott Diabetes Care Inc. | Method and device for determining elapsed sensor life |
US8461985B2 (en) | 2007-05-08 | 2013-06-11 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US8239166B2 (en) | 2007-05-14 | 2012-08-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US7996158B2 (en) | 2007-05-14 | 2011-08-09 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US10002233B2 (en) | 2007-05-14 | 2018-06-19 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8103471B2 (en) | 2007-05-14 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US9125548B2 (en) | 2007-05-14 | 2015-09-08 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8260558B2 (en) | 2007-05-14 | 2012-09-04 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8600681B2 (en) | 2007-05-14 | 2013-12-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8444560B2 (en) | 2007-05-14 | 2013-05-21 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8560038B2 (en) | 2007-05-14 | 2013-10-15 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US20200037874A1 (en) | 2007-05-18 | 2020-02-06 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
WO2008150917A1 (en) | 2007-05-31 | 2008-12-11 | Abbott Diabetes Care, Inc. | Insertion devices and methods |
WO2008157821A1 (en) | 2007-06-21 | 2008-12-24 | Abbott Diabetes Care, Inc. | Health monitor |
WO2008157820A1 (en) | 2007-06-21 | 2008-12-24 | Abbott Diabetes Care, Inc. | Health management devices and methods |
US8641618B2 (en) | 2007-06-27 | 2014-02-04 | Abbott Diabetes Care Inc. | Method and structure for securing a monitoring device element |
US8085151B2 (en) | 2007-06-28 | 2011-12-27 | Abbott Diabetes Care Inc. | Signal converting cradle for medical condition monitoring and management system |
US8160900B2 (en) | 2007-06-29 | 2012-04-17 | Abbott Diabetes Care Inc. | Analyte monitoring and management device and method to analyze the frequency of user interaction with the device |
US7768386B2 (en) | 2007-07-31 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8834366B2 (en) | 2007-07-31 | 2014-09-16 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor calibration |
US8409093B2 (en) | 2007-10-23 | 2013-04-02 | Abbott Diabetes Care Inc. | Assessing measures of glycemic variability |
US8377031B2 (en) | 2007-10-23 | 2013-02-19 | Abbott Diabetes Care Inc. | Closed loop control system with safety parameters and methods |
US8216138B1 (en) | 2007-10-23 | 2012-07-10 | Abbott Diabetes Care Inc. | Correlation of alternative site blood and interstitial fluid glucose concentrations to venous glucose concentration |
US8313527B2 (en) * | 2007-11-05 | 2012-11-20 | Allergan, Inc. | Soft prosthesis shell texturing method |
US20090164239A1 (en) | 2007-12-19 | 2009-06-25 | Abbott Diabetes Care, Inc. | Dynamic Display Of Glucose Information |
US8583204B2 (en) | 2008-03-28 | 2013-11-12 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US11730407B2 (en) | 2008-03-28 | 2023-08-22 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US8682408B2 (en) | 2008-03-28 | 2014-03-25 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
EP3659628A1 (en) | 2008-04-10 | 2020-06-03 | Abbott Diabetes Care, Inc. | Method and system for sterilizing an analyte sensor |
US8924159B2 (en) | 2008-05-30 | 2014-12-30 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
US8591410B2 (en) | 2008-05-30 | 2013-11-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
US7826382B2 (en) | 2008-05-30 | 2010-11-02 | Abbott Diabetes Care Inc. | Close proximity communication device and methods |
WO2010009172A1 (en) | 2008-07-14 | 2010-01-21 | Abbott Diabetes Care Inc. | Closed loop control system interface and methods |
US20100025238A1 (en) * | 2008-07-31 | 2010-02-04 | Medtronic Minimed, Inc. | Analyte sensor apparatuses having improved electrode configurations and methods for making and using them |
US8700114B2 (en) * | 2008-07-31 | 2014-04-15 | Medtronic Minmed, Inc. | Analyte sensor apparatuses comprising multiple implantable sensor elements and methods for making and using them |
US20100057040A1 (en) | 2008-08-31 | 2010-03-04 | Abbott Diabetes Care, Inc. | Robust Closed Loop Control And Methods |
US8734422B2 (en) | 2008-08-31 | 2014-05-27 | Abbott Diabetes Care Inc. | Closed loop control with improved alarm functions |
US8622988B2 (en) | 2008-08-31 | 2014-01-07 | Abbott Diabetes Care Inc. | Variable rate closed loop control and methods |
US9943644B2 (en) | 2008-08-31 | 2018-04-17 | Abbott Diabetes Care Inc. | Closed loop control with reference measurement and methods thereof |
EP3795987B1 (en) | 2008-09-19 | 2023-10-25 | Dexcom, Inc. | Particle-containing membrane and particulate electrode for analyte sensors |
US8986208B2 (en) | 2008-09-30 | 2015-03-24 | Abbott Diabetes Care Inc. | Analyte sensor sensitivity attenuation mitigation |
US9326707B2 (en) | 2008-11-10 | 2016-05-03 | Abbott Diabetes Care Inc. | Alarm characterization for analyte monitoring devices and systems |
US8103456B2 (en) | 2009-01-29 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and device for early signal attenuation detection using blood glucose measurements |
US8560082B2 (en) | 2009-01-30 | 2013-10-15 | Abbott Diabetes Care Inc. | Computerized determination of insulin pump therapy parameters using real time and retrospective data processing |
US20100198034A1 (en) | 2009-02-03 | 2010-08-05 | Abbott Diabetes Care Inc. | Compact On-Body Physiological Monitoring Devices and Methods Thereof |
WO2010121084A1 (en) | 2009-04-15 | 2010-10-21 | Abbott Diabetes Care Inc. | Analyte monitoring system having an alert |
WO2010121229A1 (en) | 2009-04-16 | 2010-10-21 | Abbott Diabetes Care Inc. | Analyte sensor calibration management |
WO2010127050A1 (en) | 2009-04-28 | 2010-11-04 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
WO2010129375A1 (en) | 2009-04-28 | 2010-11-11 | Abbott Diabetes Care Inc. | Closed loop blood glucose control algorithm analysis |
US8368556B2 (en) | 2009-04-29 | 2013-02-05 | Abbott Diabetes Care Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
EP2425209A4 (en) | 2009-04-29 | 2013-01-09 | Abbott Diabetes Care Inc | Method and system for providing real time analyte sensor calibration with retrospective backfill |
US20100278738A1 (en) * | 2009-05-04 | 2010-11-04 | Sitzman Thomas J | Method to detect and monitor ischemia in transplanted organs and tissues |
US9184490B2 (en) | 2009-05-29 | 2015-11-10 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
US9517023B2 (en) * | 2009-06-01 | 2016-12-13 | Profusa, Inc. | Method and system for directing a localized biological response to an implant |
US8613892B2 (en) | 2009-06-30 | 2013-12-24 | Abbott Diabetes Care Inc. | Analyte meter with a moveable head and methods of using the same |
US9351677B2 (en) | 2009-07-02 | 2016-05-31 | Dexcom, Inc. | Analyte sensor with increased reference capacity |
WO2011003036A2 (en) | 2009-07-02 | 2011-01-06 | Dexcom, Inc. | Continuous analyte sensors and methods of making same |
ES2884623T3 (en) | 2009-07-23 | 2021-12-10 | Abbott Diabetes Care Inc | Manufacturing procedure and continuous analyte measurement system |
EP2456351B1 (en) | 2009-07-23 | 2016-10-12 | Abbott Diabetes Care, Inc. | Real time management of data relating to physiological control of glucose levels |
WO2011025999A1 (en) * | 2009-08-29 | 2011-03-03 | Abbott Diabetes Care Inc. | Analyte sensor |
CA2765712A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Diabetes Care Inc. | Medical devices and methods |
WO2011026147A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
US8993331B2 (en) | 2009-08-31 | 2015-03-31 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods for managing power and noise |
EP4070729B1 (en) | 2009-08-31 | 2024-05-01 | Abbott Diabetes Care, Inc. | Displays for a medical device |
WO2011026149A1 (en) * | 2009-08-31 | 2011-03-03 | Abbott Diabetes Care Inc. | Mounting unit having a sensor and associated circuitry |
EP2482720A4 (en) | 2009-09-29 | 2014-04-23 | Abbott Diabetes Care Inc | Method and apparatus for providing notification function in analyte monitoring systems |
US20110082356A1 (en) * | 2009-10-01 | 2011-04-07 | Medtronic Minimed, Inc. | Analyte sensor apparatuses having interference rejection membranes and methods for making and using them |
EP2494323A4 (en) | 2009-10-30 | 2014-07-16 | Abbott Diabetes Care Inc | Method and apparatus for detecting false hypoglycemic conditions |
US8660628B2 (en) * | 2009-12-21 | 2014-02-25 | Medtronic Minimed, Inc. | Analyte sensors comprising blended membrane compositions and methods for making and using them |
USD924406S1 (en) | 2010-02-01 | 2021-07-06 | Abbott Diabetes Care Inc. | Analyte sensor inserter |
LT3622883T (en) | 2010-03-24 | 2021-08-25 | Abbott Diabetes Care, Inc. | Medical device inserters and processes of inserting and using medical devices |
CA2797691A1 (en) * | 2010-04-27 | 2011-11-03 | Alexei Goraltchouk | Foam-like materials and methods for producing same |
US10010272B2 (en) | 2010-05-27 | 2018-07-03 | Profusa, Inc. | Tissue-integrating electronic apparatus |
US8635046B2 (en) | 2010-06-23 | 2014-01-21 | Abbott Diabetes Care Inc. | Method and system for evaluating analyte sensor response characteristics |
US11064921B2 (en) | 2010-06-29 | 2021-07-20 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
US10092229B2 (en) | 2010-06-29 | 2018-10-09 | Abbott Diabetes Care Inc. | Calibration of analyte measurement system |
US20120165636A1 (en) * | 2010-07-22 | 2012-06-28 | Feldman Benjamin J | Systems and Methods for Improved In Vivo Analyte Sensor Function |
US9322103B2 (en) | 2010-08-06 | 2016-04-26 | Microchips Biotech, Inc. | Biosensor membrane composition, biosensor, and methods for making same |
CN103260501B (en) | 2010-10-06 | 2015-09-02 | 普罗弗萨股份有限公司 | Tissue integration sensor |
US11213226B2 (en) | 2010-10-07 | 2022-01-04 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods |
EP3583901A3 (en) | 2011-02-28 | 2020-01-15 | Abbott Diabetes Care, Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
US10136845B2 (en) | 2011-02-28 | 2018-11-27 | Abbott Diabetes Care Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
KR20130122696A (en) | 2011-03-28 | 2013-11-07 | 에프. 호프만-라 로슈 아게 | Improved diffusion layer for an enzymatic in-vivo sensor |
EP2697650B1 (en) | 2011-04-15 | 2020-09-30 | Dexcom, Inc. | Advanced analyte sensor calibration and error detection |
WO2012158202A2 (en) * | 2011-05-19 | 2012-11-22 | Abbott Diabetes Care Inc. | Analyte sensors and methods of fabricating them |
US9622691B2 (en) | 2011-10-31 | 2017-04-18 | Abbott Diabetes Care Inc. | Model based variable risk false glucose threshold alarm prevention mechanism |
WO2013066873A1 (en) | 2011-10-31 | 2013-05-10 | Abbott Diabetes Care Inc. | Electronic devices having integrated reset systems and methods thereof |
JP6443802B2 (en) | 2011-11-07 | 2018-12-26 | アボット ダイアベティス ケア インコーポレイテッドAbbott Diabetes Care Inc. | Analyte monitoring apparatus and method |
US8710993B2 (en) | 2011-11-23 | 2014-04-29 | Abbott Diabetes Care Inc. | Mitigating single point failure of devices in an analyte monitoring system and methods thereof |
US9317656B2 (en) | 2011-11-23 | 2016-04-19 | Abbott Diabetes Care Inc. | Compatibility mechanisms for devices in a continuous analyte monitoring system and methods thereof |
DK4056105T3 (en) | 2011-12-11 | 2024-01-02 | Abbott Diabetes Care Inc | Analyte sensor devices |
US10278629B2 (en) | 2012-03-12 | 2019-05-07 | University Of South Florida | Implantable biocompatible SiC sensors |
US20130267812A1 (en) | 2012-04-04 | 2013-10-10 | Dexcom, Inc. | Transcutaneous analyte sensors, applicators therefor, and associated methods |
US20130325352A1 (en) | 2012-06-05 | 2013-12-05 | Dexcom, Inc. | Calculation engine based on histograms |
US10881339B2 (en) | 2012-06-29 | 2021-01-05 | Dexcom, Inc. | Use of sensor redundancy to detect sensor failures |
US10598627B2 (en) | 2012-06-29 | 2020-03-24 | Dexcom, Inc. | Devices, systems, and methods to compensate for effects of temperature on implantable sensors |
US20140012117A1 (en) | 2012-07-09 | 2014-01-09 | Dexcom, Inc. | Systems and methods for leveraging smartphone features in continuous glucose monitoring |
EP2890297B1 (en) | 2012-08-30 | 2018-04-11 | Abbott Diabetes Care, Inc. | Dropout detection in continuous analyte monitoring data during data excursions |
US9968306B2 (en) | 2012-09-17 | 2018-05-15 | Abbott Diabetes Care Inc. | Methods and apparatuses for providing adverse condition notification with enhanced wireless communication range in analyte monitoring systems |
US20150366493A1 (en) * | 2012-09-17 | 2015-12-24 | Brains Online Holding B.V. | Rod shaped implantable biosensor |
EP2901153A4 (en) | 2012-09-26 | 2016-04-27 | Abbott Diabetes Care Inc | Method and apparatus for improving lag correction during in vivo measurement of analyte concentration with analyte concentration variability and range data |
US9788765B2 (en) | 2012-09-28 | 2017-10-17 | Dexcom, Inc. | Zwitterion surface modifications for continuous sensors |
US20140129151A1 (en) | 2012-11-07 | 2014-05-08 | Dexcom, Inc. | Systems and methods for managing glycemic variability |
US9801541B2 (en) | 2012-12-31 | 2017-10-31 | Dexcom, Inc. | Remote monitoring of analyte measurements |
US9730620B2 (en) | 2012-12-31 | 2017-08-15 | Dexcom, Inc. | Remote monitoring of analyte measurements |
EP4235684A1 (en) | 2013-03-14 | 2023-08-30 | Dexcom, Inc. | Systems and methods for processing and transmitting sensor data |
CN113274007A (en) | 2013-03-14 | 2021-08-20 | 普罗菲尤萨股份有限公司 | Method and apparatus for correcting optical signals |
US10335075B2 (en) | 2013-03-14 | 2019-07-02 | Dexcom, Inc. | Advanced calibration for analyte sensors |
US9788354B2 (en) | 2013-03-14 | 2017-10-10 | Dexcom, Inc. | Systems and methods for processing and transmitting sensor data |
US9474475B1 (en) | 2013-03-15 | 2016-10-25 | Abbott Diabetes Care Inc. | Multi-rate analyte sensor data collection with sample rate configurable signal processing |
US10433773B1 (en) | 2013-03-15 | 2019-10-08 | Abbott Diabetes Care Inc. | Noise rejection methods and apparatus for sparsely sampled analyte sensor data |
US9737250B2 (en) | 2013-03-15 | 2017-08-22 | Dexcom, Inc. | Membrane for continuous analyte sensors |
WO2014152034A1 (en) | 2013-03-15 | 2014-09-25 | Abbott Diabetes Care Inc. | Sensor fault detection using analyte sensor data pattern comparison |
EP3777656A1 (en) | 2013-06-06 | 2021-02-17 | Profusa, Inc. | Apparatus for detecting optical signals from implanted sensors |
US9763605B2 (en) * | 2013-11-27 | 2017-09-19 | Verily Life Sciences Llc | Adjustment of sensor sensitivity by controlling copolymer film thickness through a controlled drying step |
US20150160151A1 (en) * | 2013-12-06 | 2015-06-11 | Google Inc. | Formulation and Storage Method to Enhance the Enzyme and Sensor Stabilities |
US9617578B2 (en) | 2013-12-06 | 2017-04-11 | Verily Life Sciences Llc | Sensor membrane with low temperature coefficient |
US9855359B2 (en) | 2013-12-23 | 2018-01-02 | Verily Life Sciences Llc | Analyte sensors with ethylene oxide immunity |
US9739746B1 (en) | 2013-12-23 | 2017-08-22 | Google Inc. | Analyte sensor incorporating negatively charged moieties |
RU2683203C2 (en) | 2013-12-31 | 2019-03-26 | Эбботт Дайабитиз Кэр Инк. | Self-powered analyte sensor and devices using the same |
WO2015153482A1 (en) | 2014-03-30 | 2015-10-08 | Abbott Diabetes Care Inc. | Method and apparatus for determining meal start and peak events in analyte monitoring systems |
WO2015156966A1 (en) | 2014-04-10 | 2015-10-15 | Dexcom, Inc. | Sensors for continuous analyte monitoring, and related methods |
USD749440S1 (en) * | 2014-05-30 | 2016-02-16 | Yepzon Oy | Locating and tracking device |
WO2016014987A2 (en) | 2014-07-24 | 2016-01-28 | Thomas Jefferson University | Long-term implantable monitoring system & methods of use |
WO2016109163A1 (en) | 2014-12-31 | 2016-07-07 | Theranova, Llc | Methods and devices for analyte sensing in potential spaces |
US10864367B2 (en) | 2015-02-24 | 2020-12-15 | Elira, Inc. | Methods for using an electrical dermal patch in a manner that reduces adverse patient reactions |
US10376145B2 (en) | 2015-02-24 | 2019-08-13 | Elira, Inc. | Systems and methods for enabling a patient to achieve a weight loss objective using an electrical dermal patch |
US10335302B2 (en) | 2015-02-24 | 2019-07-02 | Elira, Inc. | Systems and methods for using transcutaneous electrical stimulation to enable dietary interventions |
US10765863B2 (en) | 2015-02-24 | 2020-09-08 | Elira, Inc. | Systems and methods for using a transcutaneous electrical stimulation device to deliver titrated therapy |
US20220062621A1 (en) | 2015-02-24 | 2022-03-03 | Elira, Inc. | Electrical Stimulation-Based Weight Management System |
CN115227969A (en) | 2015-02-24 | 2022-10-25 | 伊莱拉股份有限公司 | Method for achieving appetite regulation or improving dietary compliance using electrode patches |
US9956393B2 (en) | 2015-02-24 | 2018-05-01 | Elira, Inc. | Systems for increasing a delay in the gastric emptying time for a patient using a transcutaneous electro-dermal patch |
US10213139B2 (en) | 2015-05-14 | 2019-02-26 | Abbott Diabetes Care Inc. | Systems, devices, and methods for assembling an applicator and sensor control device |
EP3294134B1 (en) | 2015-05-14 | 2020-07-08 | Abbott Diabetes Care Inc. | Inserter system for a compact medical device and corresponding method |
WO2016196516A1 (en) | 2015-06-03 | 2016-12-08 | William Kenneth Ward | Measurement of glucose in an insulin delivery catheter by minimizing the adverse effects of insulin preservatives |
CA2991716A1 (en) | 2015-07-10 | 2017-01-19 | Abbott Diabetes Care Inc. | System, device and method of dynamic glucose profile response to physiological parameters |
US10079835B1 (en) * | 2015-09-28 | 2018-09-18 | Symantec Corporation | Systems and methods for data loss prevention of unidentifiable and unsupported object types |
US20170112533A1 (en) | 2015-10-21 | 2017-04-27 | Dexcom, Inc. | Transcutaneous analyte sensors, applicators therefor, and associated methods |
CA2998396A1 (en) * | 2015-12-21 | 2017-06-29 | Dexcom, Inc. | Continuous analyte monitoring system power conservation |
US10932672B2 (en) | 2015-12-28 | 2021-03-02 | Dexcom, Inc. | Systems and methods for remote and host monitoring communications |
US11112377B2 (en) | 2015-12-30 | 2021-09-07 | Dexcom, Inc. | Enzyme immobilized adhesive layer for analyte sensors |
ES2917419T3 (en) | 2016-03-31 | 2022-07-08 | Dexcom Inc | Communication systems between a sensor electronics unit and a display device of an analyte monitoring system |
US9913042B2 (en) * | 2016-06-14 | 2018-03-06 | Bose Corporation | Miniature device having an acoustic diaphragm |
WO2018119400A1 (en) | 2016-12-22 | 2018-06-28 | Profusa, Inc. | System and single-channel luminescent sensor for and method of determining analyte value |
EP3570748B1 (en) | 2017-01-19 | 2024-01-17 | Dexcom, Inc. | Flexible analyte sensors |
CA3050721A1 (en) | 2017-01-23 | 2018-07-26 | Abbott Diabetes Care Inc. | Systems, devices and methods for analyte sensor insertion |
EP3600014A4 (en) | 2017-03-21 | 2020-10-21 | Abbott Diabetes Care Inc. | Methods, devices and system for providing diabetic condition diagnosis and therapy |
WO2018184012A1 (en) | 2017-03-31 | 2018-10-04 | Capillary Biomedical, Inc. | Helical insertion infusion device |
KR102693461B1 (en) | 2017-06-23 | 2024-08-07 | 덱스콤, 인크. | Transdermal analytical sensor, applicator therefor and related method |
US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
US20190120785A1 (en) | 2017-10-24 | 2019-04-25 | Dexcom, Inc. | Pre-connected analyte sensors |
USD926325S1 (en) | 2018-06-22 | 2021-07-27 | Dexcom, Inc. | Wearable medical monitoring device |
US20210355312A1 (en) | 2018-09-27 | 2021-11-18 | l-SENS, INC. | Polymer blend for controlling blood glucose influx, and continuous glucose monitoring biosensor comprising same |
WO2020146106A1 (en) * | 2019-01-09 | 2020-07-16 | California Institute Of Technology | Implantable micro-sensor to quantify dissolved inert gas |
USD1002852S1 (en) | 2019-06-06 | 2023-10-24 | Abbott Diabetes Care Inc. | Analyte sensor device |
EP3998936A4 (en) | 2019-07-17 | 2022-08-31 | Nxgenport, L.L.C. | Implantable venous access port with remote physiological monitoring capabilities |
WO2021195571A1 (en) | 2020-03-27 | 2021-09-30 | Poragen LLC | Biocompatible porous materials and methods of manufacture and use |
USD999913S1 (en) | 2020-12-21 | 2023-09-26 | Abbott Diabetes Care Inc | Analyte sensor inserter |
JP2023117729A (en) * | 2022-02-14 | 2023-08-24 | アークレイ株式会社 | Glucose measurement electrode and electrochemical sensor including the same |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060020192A1 (en) * | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
Family Cites Families (731)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19852258A1 (en) | 1998-11-11 | 2000-05-18 | Agfa Gevaert Ag | Radiation-sensitive recording material for the production of waterless offset printing plates |
US1579806A (en) | 1922-02-04 | 1926-04-06 | Technicolor Motion Picture | Registration of complemental images in cinematography |
US2830020A (en) | 1956-10-01 | 1958-04-08 | American Cyanamid Co | Lubricating oils thickened with metal salts of cyanuric acid |
US3220960A (en) | 1960-12-21 | 1965-11-30 | Wichterle Otto | Cross-linked hydrophilic polymers and articles made therefrom |
US3562352A (en) * | 1968-09-06 | 1971-02-09 | Avco Corp | Polysiloxane-polyurethane block copolymers |
US3607329A (en) | 1969-04-22 | 1971-09-21 | Us Interior | Cellulose acetate butyrate semipermeable membranes and their production |
US3746588A (en) | 1971-03-29 | 1973-07-17 | Aerojet General Co | Sterilization of nitroparaffin-amine explosives |
GB1412983A (en) * | 1971-11-30 | 1975-11-05 | Debell & Richardson | Method of producing porous plastic materials |
US3943918A (en) | 1971-12-02 | 1976-03-16 | Tel-Pac, Inc. | Disposable physiological telemetric device |
US3837339A (en) | 1972-02-03 | 1974-09-24 | Whittaker Corp | Blood glucose level monitoring-alarm system and method therefor |
US3874850A (en) | 1972-07-24 | 1975-04-01 | Radiometer As | Blood analyzing method and apparatus |
US3908657A (en) * | 1973-01-15 | 1975-09-30 | Univ Johns Hopkins | System for continuous withdrawal of blood |
US3926760A (en) | 1973-09-28 | 1975-12-16 | Du Pont | Process for electrophoretic deposition of polymer |
US4267145A (en) | 1974-01-03 | 1981-05-12 | E. I. Du Pont De Nemours And Company | Process for preparing cold water-soluble films from PVA by melt extrusion |
US3898984A (en) | 1974-02-04 | 1975-08-12 | Us Navy | Ambulatory patient monitoring system |
US3966580A (en) | 1974-09-16 | 1976-06-29 | The University Of Utah | Novel protein-immobilizing hydrophobic polymeric membrane, process for producing same and apparatus employing same |
US3979274A (en) * | 1975-09-24 | 1976-09-07 | The Yellow Springs Instrument Company, Inc. | Membrane for enzyme electrodes |
CH591237A5 (en) | 1975-11-06 | 1977-09-15 | Bbc Brown Boveri & Cie | |
US4016866A (en) | 1975-12-18 | 1977-04-12 | General Electric Company | Implantable electrochemical sensor |
US4040908A (en) | 1976-03-12 | 1977-08-09 | Children's Hospital Medical Center | Polarographic analysis of cholesterol and other macromolecular substances |
US4024312A (en) | 1976-06-23 | 1977-05-17 | Johnson & Johnson | Pressure-sensitive adhesive tape having extensible and elastic backing composed of a block copolymer |
JPS5920961B2 (en) | 1976-11-30 | 1984-05-16 | 東北金属工業株式会社 | Pulsar |
US4136250A (en) * | 1977-07-20 | 1979-01-23 | Ciba-Geigy Corporation | Polysiloxane hydrogels |
JPS5921500B2 (en) | 1978-01-28 | 1984-05-21 | 東洋紡績株式会社 | Enzyme membrane for oxygen electrode |
DE2820474C2 (en) | 1978-05-10 | 1983-11-10 | Fresenius AG, 6380 Bad Homburg | Electrochemical probe |
US4292423A (en) | 1979-04-19 | 1981-09-29 | Wacker-Chemie Gmbh | Process for the preparation of organopolysiloxanes |
US4253469A (en) | 1979-04-20 | 1981-03-03 | The Narda Microwave Corporation | Implantable temperature probe |
JPS5627643A (en) | 1979-08-14 | 1981-03-18 | Toshiba Corp | Electrochemical measuring device |
US4260725A (en) | 1979-12-10 | 1981-04-07 | Bausch & Lomb Incorporated | Hydrophilic contact lens made from polysiloxanes which are thermally bonded to polymerizable groups and which contain hydrophilic sidechains |
US4403984A (en) | 1979-12-28 | 1983-09-13 | Biotek, Inc. | System for demand-based adminstration of insulin |
US5120813A (en) | 1980-02-29 | 1992-06-09 | Th. Goldschmidt Ag | Moisture vapor permeable materials |
US4861830A (en) | 1980-02-29 | 1989-08-29 | Th. Goldschmidt Ag | Polymer systems suitable for blood-contacting surfaces of a biomedical device, and methods for forming |
US4686137A (en) | 1980-02-29 | 1987-08-11 | Thoratec Laboratories Corp. | Moisture vapor permeable materials |
US4356074A (en) * | 1980-08-25 | 1982-10-26 | The Yellow Springs Instrument Company, Inc. | Substrate specific galactose oxidase enzyme electrodes |
EP0047013B1 (en) | 1980-09-02 | 1986-01-22 | Medtronic, Inc. | Subcutaneously implantable lead with drug dispenser means |
IE51643B1 (en) | 1980-10-15 | 1987-01-21 | Smith & Nephew Ass | Coated articles and materials suitable for coating |
US4327725A (en) | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
JPS5929693Y2 (en) | 1980-12-25 | 1984-08-25 | オリンパス光学工業株式会社 | Cell collection device for endoscope |
JPS57118152A (en) * | 1981-01-14 | 1982-07-22 | Matsushita Electric Ind Co Ltd | Enzyme electrode |
JPS57156004A (en) | 1981-03-20 | 1982-09-27 | Nitto Electric Ind Co Ltd | Gas separating membrane |
JPS57156005A (en) | 1981-03-20 | 1982-09-27 | Nitto Electric Ind Co Ltd | Selective permeable membrane |
JPS57156005U (en) | 1981-03-26 | 1982-09-30 | ||
JPS57156004U (en) | 1981-03-26 | 1982-09-30 | ||
US4442841A (en) | 1981-04-30 | 1984-04-17 | Mitsubishi Rayon Company Limited | Electrode for living bodies |
US4453537A (en) | 1981-08-04 | 1984-06-12 | Spitzer Daniel E | Apparatus for powering a body implant device |
DE3278334D1 (en) | 1981-10-23 | 1988-05-19 | Genetics Int Inc | Sensor for components of a liquid mixture |
US4415666A (en) | 1981-11-05 | 1983-11-15 | Miles Laboratories, Inc. | Enzyme electrode membrane |
US4418148A (en) | 1981-11-05 | 1983-11-29 | Miles Laboratories, Inc. | Multilayer enzyme electrode membrane |
US4454295A (en) | 1981-11-16 | 1984-06-12 | Uco Optics, Inc. | Cured cellulose ester, method of curing same, and use thereof |
JPS5886172A (en) | 1981-11-18 | 1983-05-23 | テルモ株式会社 | Medical substance moving apparatus |
US4494950A (en) * | 1982-01-19 | 1985-01-22 | The Johns Hopkins University | Plural module medication delivery system |
US4482666A (en) | 1982-03-12 | 1984-11-13 | Apace Research Limited | Emulsions of liquid hydrocarbons with water and/or alcohols |
JPS58163402A (en) | 1982-03-20 | 1983-09-28 | Nitto Electric Ind Co Ltd | Gas separation membrane |
JPS58163403A (en) | 1982-03-23 | 1983-09-28 | Nitto Electric Ind Co Ltd | Gas separation membrane |
US4493714A (en) * | 1982-05-06 | 1985-01-15 | Teijin Limited | Ultrathin film, process for production thereof, and use thereof for concentrating a specified gas in a gaseous mixture |
FR2528693B1 (en) * | 1982-06-22 | 1985-01-11 | Mabille Pierre | DENTAL PROPHYLAXIS DEVICE |
JPS5929693A (en) | 1982-08-10 | 1984-02-16 | Asahi Glass Co Ltd | Fluorine-containing diisocyanate containing siloxane bond |
JPS5949805A (en) | 1982-09-17 | 1984-03-22 | Teijin Ltd | Permselective membrane for separation of gas |
JPS5949803A (en) | 1982-09-17 | 1984-03-22 | Teijin Ltd | Permselective membrane for separation of gas |
JPS5949803U (en) | 1982-09-27 | 1984-04-02 | リンナイ株式会社 | Oven cooking device operating device |
JPS5949805U (en) | 1982-09-27 | 1984-04-02 | 株式会社東芝 | High frequency heating cooking device |
JPS5959221A (en) | 1982-09-29 | 1984-04-05 | Teijin Ltd | Prearation of composite perrmeable membrane for separating gas |
JPS5959221U (en) | 1982-10-12 | 1984-04-18 | 和光産業株式会社 | Plate fixing device in multi-blade fan assembly machine |
JPS591929Y2 (en) | 1982-10-25 | 1984-01-19 | ロ−レルバンクマシン株式会社 | Cumulative coin support rod of coin wrapping machine |
AU573730B2 (en) | 1982-10-25 | 1988-06-23 | Antarctic Pharma Ab | Enzyme composition from euphausiaceae (antarctic krill) as cleaning agent |
JPS5987004A (en) | 1982-11-08 | 1984-05-19 | Nitto Electric Ind Co Ltd | Gas separation membrane |
JPS58163403U (en) | 1982-11-27 | 1983-10-31 | ナイガイ株式会社 | Single drive source packaging machine |
JPS5987004U (en) | 1982-12-01 | 1984-06-12 | 古河電気工業株式会社 | Airtight penetration for optical transmission line |
JPS59128406U (en) | 1983-02-19 | 1984-08-29 | 倉敷化工株式会社 | Suspension rubber bushing for automobiles |
US4506680A (en) | 1983-03-17 | 1985-03-26 | Medtronic, Inc. | Drug dispensing body implantable lead |
CA1247960A (en) | 1983-03-24 | 1989-01-03 | Hideki Aoki | Transcutaneously implantable element |
CA1219040A (en) | 1983-05-05 | 1987-03-10 | Elliot V. Plotkin | Measurement of enzyme-catalysed reactions |
JPS59209608A (en) | 1983-05-12 | 1984-11-28 | Teijin Ltd | Permselective membrane |
JPS59209609A (en) | 1983-05-12 | 1984-11-28 | Teijin Ltd | Permselective membrane |
JPS59209610A (en) | 1983-05-12 | 1984-11-28 | Teijin Ltd | Permselective membrane |
JPS59211459A (en) | 1983-05-17 | 1984-11-30 | 帝人株式会社 | Pasturization of blood treating device |
US4650547A (en) | 1983-05-19 | 1987-03-17 | The Regents Of The University Of California | Method and membrane applicable to implantable sensor |
US4484987A (en) | 1983-05-19 | 1984-11-27 | The Regents Of The University Of California | Method and membrane applicable to implantable sensor |
US4675346A (en) | 1983-06-20 | 1987-06-23 | Loctite Corporation | UV curable silicone rubber compositions |
US4663824A (en) | 1983-07-05 | 1987-05-12 | Matsushita Electric Industrial Co., Ltd. | Aluminum electrolytic capacitor and a manufacturing method therefor |
US4538616A (en) | 1983-07-25 | 1985-09-03 | Robert Rogoff | Blood sugar level sensing and monitoring transducer |
US4565665A (en) * | 1983-08-03 | 1986-01-21 | Medtronic, Inc. | Flow through ion selective electrode |
US4600495A (en) | 1983-08-03 | 1986-07-15 | Medtronic, Inc. | Flow through ion selective electrode |
US4565666A (en) * | 1983-08-03 | 1986-01-21 | Medtronic, Inc. | Method of producing combination ion selective sensing electrode |
US4519973A (en) | 1983-08-03 | 1985-05-28 | Medtronic, Inc. | Ion selective membranes for use in ion sensing electrodes |
US4486290A (en) | 1983-08-03 | 1984-12-04 | Medtronic, Inc. | Combination ion selective sensing electrode |
US4554927A (en) | 1983-08-30 | 1985-11-26 | Thermometrics Inc. | Pressure and temperature sensor |
JPS6084530A (en) | 1983-10-17 | 1985-05-13 | Hitachi Ltd | Liquid crystal display element |
US4867741A (en) | 1983-11-04 | 1989-09-19 | Portnoy Harold D | Physiological draining system with differential pressure and compensating valves |
JPS60146219A (en) | 1984-01-11 | 1985-08-01 | Toray Ind Inc | Contact lens |
US4739380A (en) | 1984-01-19 | 1988-04-19 | Integrated Ionics, Inc. | Integrated ambient sensing devices and methods of manufacture |
JPS60136214U (en) | 1984-02-23 | 1985-09-10 | いすゞ自動車株式会社 | Height adjustment device for vehicles with air spring suspension |
US4527999A (en) | 1984-03-23 | 1985-07-09 | Abcor, Inc. | Separation membrane and method of preparing and using same |
JPS60231156A (en) * | 1984-04-30 | 1985-11-16 | Kuraray Co Ltd | Liquid junction type reference electrode |
US4753652A (en) | 1984-05-04 | 1988-06-28 | Children's Medical Center Corporation | Biomaterial implants which resist calcification |
JPS60245623A (en) | 1984-05-18 | 1985-12-05 | Nippon Yunikaa Kk | Production of flexible polyether-urethane foam of low gas permeability |
US4644046A (en) * | 1984-06-20 | 1987-02-17 | Teijin Limited | Ultrathin film, process for production thereof, and use thereof for concentrating a specific gas from a gas mixture |
CA1258496A (en) | 1984-07-30 | 1989-08-15 | Teruyoshi Uchida | Insulated noble metal wire and porous membrane as po.sub.2 bioelectrode |
AU592772B2 (en) | 1984-09-05 | 1990-01-25 | Vaso Products Australia Pty. Limited | Control of blood flow |
US5171689A (en) | 1984-11-08 | 1992-12-15 | Matsushita Electric Industrial Co., Ltd. | Solid state bio-sensor |
US4602922A (en) | 1984-11-09 | 1986-07-29 | Research Foundation Of State University Of New York | Method of making membranes for gas separation and the composite membranes |
US4702732A (en) | 1984-12-24 | 1987-10-27 | Trustees Of Boston University | Electrodes, electrode assemblies, methods, and systems for tissue stimulation and transdermal delivery of pharmacologically active ligands |
US5235003A (en) | 1985-01-04 | 1993-08-10 | Thoratec Laboratories Corporation | Polysiloxane-polylactone block copolymers |
US4963595A (en) | 1985-01-04 | 1990-10-16 | Thoratec Laboratories Corporation | Polysiloxane-polylactone block copolymers |
US4577642A (en) | 1985-02-27 | 1986-03-25 | Medtronic, Inc. | Drug dispensing body implantable lead employing molecular sieves and methods of fabrication |
JPS61232859A (en) | 1985-04-05 | 1986-10-17 | 呉羽化学工業株式会社 | Medical pump apparatus |
JPS61238319A (en) | 1985-04-17 | 1986-10-23 | Dainippon Ink & Chem Inc | Selective gas permeable membrane |
GB8514176D0 (en) | 1985-06-05 | 1985-07-10 | Ici Plc | Membrane |
US4671288A (en) | 1985-06-13 | 1987-06-09 | The Regents Of The University Of California | Electrochemical cell sensor for continuous short-term use in tissues and blood |
US4938860A (en) | 1985-06-28 | 1990-07-03 | Miles Inc. | Electrode for electrochemical sensors |
US4592824A (en) | 1985-09-13 | 1986-06-03 | Centre Suisse D'electronique Et De Microtechnique S.A. | Miniature liquid junction reference electrode and an integrated solid state electrochemical sensor including the same |
US4680268A (en) * | 1985-09-18 | 1987-07-14 | Children's Hospital Medical Center | Implantable gas-containing biosensor and method for measuring an analyte such as glucose |
US4890620A (en) * | 1985-09-20 | 1990-01-02 | The Regents Of The University Of California | Two-dimensional diffusion glucose substrate sensing electrode |
JPS6274406A (en) | 1985-09-30 | 1987-04-06 | Teijin Ltd | Separating membrane |
US4689309A (en) | 1985-09-30 | 1987-08-25 | Miles Laboratories, Inc. | Test device, method of manufacturing same and method of determining a component in a sample |
JPS6274406U (en) | 1985-10-29 | 1987-05-13 | ||
JPS62102815A (en) | 1985-10-30 | 1987-05-13 | Agency Of Ind Science & Technol | Gas permselective membrane |
US4647643A (en) | 1985-11-08 | 1987-03-03 | Becton, Dickinson And Company | Soft non-blocking polyurethanes |
JPH0341047Y2 (en) | 1985-12-19 | 1991-08-29 | ||
US4684538A (en) | 1986-02-21 | 1987-08-04 | Loctite Corporation | Polysiloxane urethane compounds and adhesive compositions, and method of making and using the same |
US4776944A (en) | 1986-03-20 | 1988-10-11 | Jiri Janata | Chemical selective sensors utilizing admittance modulated membranes |
JPS62225513A (en) * | 1986-03-26 | 1987-10-03 | Shin Etsu Chem Co Ltd | Block-graft copolymer and production thereof |
JPH0696106B2 (en) | 1986-03-31 | 1994-11-30 | 帝人株式会社 | Gas separation membrane |
US4685463A (en) | 1986-04-03 | 1987-08-11 | Williams R Bruce | Device for continuous in vivo measurement of blood glucose concentrations |
JPS62240025A (en) | 1986-04-10 | 1987-10-20 | 住友電気工業株式会社 | Catheter type sensor |
US4994167A (en) * | 1986-04-15 | 1991-02-19 | Markwell Medical Institute, Inc. | Biological fluid measuring device |
US4757022A (en) | 1986-04-15 | 1988-07-12 | Markwell Medical Institute, Inc. | Biological fluid measuring device |
US4795542A (en) * | 1986-04-24 | 1989-01-03 | St. Jude Medical, Inc. | Electrochemical concentration detector device |
US4909908A (en) | 1986-04-24 | 1990-03-20 | Pepi Ross | Electrochemical cncentration detector method |
US4703756A (en) | 1986-05-06 | 1987-11-03 | The Regents Of The University Of California | Complete glucose monitoring system with an implantable, telemetered sensor module |
US4731726A (en) | 1986-05-19 | 1988-03-15 | Healthware Corporation | Patient-operated glucose monitor and diabetes management system |
GB8612861D0 (en) | 1986-05-27 | 1986-07-02 | Cambridge Life Sciences | Immobilised enzyme biosensors |
US4763658A (en) | 1986-06-04 | 1988-08-16 | Solutech, Inc. | Dialysis system 2nd method |
US4726381A (en) * | 1986-06-04 | 1988-02-23 | Solutech, Inc. | Dialysis system and method |
US4781733A (en) | 1986-07-23 | 1988-11-01 | Bend Research, Inc. | Semipermeable thin-film membranes comprising siloxane, alkoxysilyl and aryloxysilyl oligomers and copolymers |
US5002572A (en) | 1986-09-11 | 1991-03-26 | Picha George J | Biological implant with textured surface |
AU617667B2 (en) | 1986-11-04 | 1991-12-05 | Allergan, Inc. | Open-cell, silicone-elastomer medical implant and method for making |
US5007929B1 (en) | 1986-11-04 | 1994-08-30 | Medical Products Dev | Open-cell silicone-elastomer medical implant |
JPS63130661A (en) | 1986-11-20 | 1988-06-02 | Toppan Printing Co Ltd | Non-porous moisture-permeable waterproof film |
FR2607696B1 (en) * | 1986-12-03 | 1995-08-11 | Gosserez Olivier | IMPLANTABLE BREAST PROSTHESIS CONTRARY TO THE FORMATION OF A RETRACTILE SHELL |
EP0273258B1 (en) | 1986-12-22 | 1991-11-21 | Siemens Aktiengesellschaft | Arrangement for the analysis of liquids, and method of applying it |
US4694861A (en) | 1986-12-22 | 1987-09-22 | Beckman Instruments, Inc. | Rotary pinch valve |
DE3700119A1 (en) | 1987-01-03 | 1988-07-14 | Inst Diabetestechnologie Gemei | IMPLANTABLE ELECTROCHEMICAL SENSOR |
JPS63130661U (en) | 1987-02-18 | 1988-08-26 | ||
US4854322A (en) | 1987-02-25 | 1989-08-08 | Ash Medical Systems, Inc. | Capillary filtration and collection device for long-term monitoring of blood constituents |
US4777953A (en) | 1987-02-25 | 1988-10-18 | Ash Medical Systems, Inc. | Capillary filtration and collection method for long-term monitoring of blood constituents |
US4851088A (en) * | 1987-03-05 | 1989-07-25 | Honeywell Inc. | Electrochemical detection of carbon dioxide |
US4935345A (en) | 1987-04-07 | 1990-06-19 | Arizona Board Of Regents | Implantable microelectronic biochemical sensor incorporating thin film thermopile |
US4759828A (en) | 1987-04-09 | 1988-07-26 | Nova Biomedical Corporation | Glucose electrode and method of determining glucose |
US5352348A (en) | 1987-04-09 | 1994-10-04 | Nova Biomedical Corporation | Method of using enzyme electrode |
US4832034A (en) | 1987-04-09 | 1989-05-23 | Pizziconi Vincent B | Method and apparatus for withdrawing, collecting and biosensing chemical constituents from complex fluids |
IT1215491B (en) | 1987-05-15 | 1990-02-14 | Enricerche Spa | BIOSENSOR WITH ENZYMATIC MEMBRANE CHEMICALLY CONNECTED TO A SEMICONDUCTIVE DEVICE. |
US4820281A (en) | 1987-05-21 | 1989-04-11 | Ivy Medical, Inc. | Drop volume measurement system |
US4880883A (en) | 1987-06-03 | 1989-11-14 | Wisconsin Alumni Research Foundation | Biocompatible polyurethanes modified with lower alkyl sulfonate and lower alkyl carboxylate |
US5286364A (en) * | 1987-06-08 | 1994-02-15 | Rutgers University | Surface-modified electochemical biosensor |
US4810470A (en) | 1987-06-19 | 1989-03-07 | Miles Inc. | Volume independent diagnostic device |
US4834101A (en) | 1987-06-26 | 1989-05-30 | The University Of Michigan | Catheter-type electrochemical sensors |
US4786657A (en) | 1987-07-02 | 1988-11-22 | Minnesota Mining And Manufacturing Company | Polyurethanes and polyurethane/polyureas crosslinked using 2-glyceryl acrylate or 2-glyceryl methacrylate |
JPH07122624B2 (en) | 1987-07-06 | 1995-12-25 | ダイキン工業株式会社 | Biosensor |
US4805625A (en) * | 1987-07-08 | 1989-02-21 | Ad-Tech Medical Instrument Corporation | Sphenoidal electrode and insertion method |
FI77569C (en) | 1987-07-13 | 1989-04-10 | Huhtamaeki Oy | ANORDINATION FOR THE PURPOSE OF THE OPERATIONS AND THE OPERATIONS OF ELLER EN VAEVNAD. |
JPH07114937B2 (en) | 1987-07-13 | 1995-12-13 | 帝人株式会社 | Separation membrane |
JPH0824830B2 (en) | 1987-07-13 | 1996-03-13 | 帝人株式会社 | Separation membrane |
DE3725728A1 (en) | 1987-08-04 | 1989-02-16 | Freudenberg Carl Fa | MEDICAL DEVICE AND METHOD FOR THE PRODUCTION THEREOF |
US5221724A (en) | 1987-08-12 | 1993-06-22 | Wisconsin Alumni Research Foundation | Polysiloxane polyurea urethanes |
GB2209836A (en) | 1987-09-16 | 1989-05-24 | Cambridge Life Sciences | Multilayer enzyme electrode membrane and method of making same |
US4974929A (en) | 1987-09-22 | 1990-12-04 | Baxter International, Inc. | Fiber optical probe connector for physiologic measurement devices |
NL8702370A (en) | 1987-10-05 | 1989-05-01 | Groningen Science Park | METHOD AND SYSTEM FOR GLUCOSE DETERMINATION AND USEABLE MEASURING CELL ASSEMBLY. |
DE3736652A1 (en) | 1987-10-29 | 1989-05-11 | Bayer Ag | PROCESS FOR PREPARING COATINGS |
US5242835A (en) | 1987-11-03 | 1993-09-07 | Radiometer A/S | Method and apparatus for determining the concentration of oxygen |
GB8725936D0 (en) | 1987-11-05 | 1987-12-09 | Genetics Int Inc | Sensing system |
US5128408A (en) | 1987-11-16 | 1992-07-07 | Toyo Boseki Kabushiki Kaisha | Gas-permeable material with excellent compatibility with blood |
US5773286A (en) | 1987-11-17 | 1998-06-30 | Cytotherapeutics, Inc. | Inner supported biocompatible cell capsules |
US4852573A (en) | 1987-12-04 | 1989-08-01 | Kennedy Philip R | Implantable neural electrode |
US4813424A (en) | 1987-12-23 | 1989-03-21 | University Of New Mexico | Long-life membrane electrode for non-ionic species |
US5362307A (en) | 1989-01-24 | 1994-11-08 | The Regents Of The University Of California | Method for the iontophoretic non-invasive-determination of the in vivo concentration level of an inorganic or organic substance |
US5070169A (en) | 1988-02-26 | 1991-12-03 | Ciba-Geigy Corporation | Wettable, flexible, oxygen permeable contact lens containing block copolymer polysiloxane-polyoxyalkylene backbone units and use thereof |
US4934375A (en) | 1988-03-04 | 1990-06-19 | Spectramed, Inc. | Flush-valve assembly for blood pressure measurement catheter |
US4822336A (en) | 1988-03-04 | 1989-04-18 | Ditraglia John | Blood glucose level sensing |
US4793555A (en) | 1988-04-22 | 1988-12-27 | Dow Corning Corporation | Container, method and composition for controlling the release of a volatile liquid from an aqueous mixture |
US4951657A (en) | 1988-04-22 | 1990-08-28 | Dow Corning Corporation | Heat sealable membrane for transdermal drug release |
US4908208A (en) | 1988-04-22 | 1990-03-13 | Dow Corning Corporation | Matrix for release of active ingredients |
US4952618A (en) | 1988-05-03 | 1990-08-28 | Minnesota Mining And Manufacturing Company | Hydrocolloid/adhesive composition |
US5342693A (en) | 1988-06-08 | 1994-08-30 | Cardiopulmonics, Inc. | Multifunctional thrombo-resistant coating and methods of manufacture |
US4849458A (en) | 1988-06-17 | 1989-07-18 | Matrix Medica, Inc. | Segmented polyether polyurethane |
CA1299653C (en) | 1988-07-07 | 1992-04-28 | Markwell Medical Institute, Inc. | Biological fluid measuring device |
US4907857A (en) | 1988-07-25 | 1990-03-13 | Abbott Laboratories | Optical fiber distribution system for an optical fiber sensor |
EP0353328A1 (en) | 1988-08-03 | 1990-02-07 | Dräger Nederland B.V. | A polarographic-amperometric three-electrode sensor |
US4994026A (en) * | 1988-08-31 | 1991-02-19 | W. R. Grace & Co.-Conn. | Gravity flow fluid balance system |
US5438984A (en) | 1988-09-08 | 1995-08-08 | Sudor Partners | Apparatus and method for the collection of analytes on a dermal patch |
US4960594A (en) | 1988-09-22 | 1990-10-02 | Derma-Lock Medical Corporation | Polyurethane foam dressing |
US4983702A (en) | 1988-09-28 | 1991-01-08 | Ciba-Geigy Corporation | Crosslinked siloxane-urethane polymer contact lens |
US5200051A (en) | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US5212050A (en) | 1988-11-14 | 1993-05-18 | Mier Randall M | Method of forming a permselective layer |
US5063081A (en) | 1988-11-14 | 1991-11-05 | I-Stat Corporation | Method of manufacturing a plurality of uniform microfabricated sensing devices having an immobilized ligand receptor |
US6306594B1 (en) | 1988-11-14 | 2001-10-23 | I-Stat Corporation | Methods for microdispensing patterened layers |
US5009251A (en) | 1988-11-15 | 1991-04-23 | Baxter International, Inc. | Fluid flow control |
US5006050A (en) | 1988-12-09 | 1991-04-09 | James E. Cooke | High accuracy disposable cassette infusion pump |
JPH073321Y2 (en) * | 1988-12-10 | 1995-01-30 | 株式会社堀場製作所 | Flow-through hydrogen peroxide electrode |
WO1990007575A1 (en) | 1988-12-30 | 1990-07-12 | Anderson David M | Stabilized microporous materials and hydrogel materials |
US5458631A (en) | 1989-01-06 | 1995-10-17 | Xavier; Ravi | Implantable catheter with electrical pulse nerve stimulators and drug delivery system |
US4967940A (en) | 1989-02-21 | 1990-11-06 | Minnesota Mining And Manufacturing Co. | Method and apparatus for precision squeeze tube valving, pumping and dispensing of work fluid(s) |
US5269891A (en) | 1989-03-09 | 1993-12-14 | Novo Nordisk A/S | Method and apparatus for determination of a constituent in a fluid |
JPH02298855A (en) | 1989-03-20 | 1990-12-11 | Assoc Univ Inc | Electrochemical biosensor using immobilized enzyme and redox polymer |
CA1328359C (en) * | 1989-03-27 | 1994-04-12 | Michael D. Mintz | Fluid sample collection and delivery system and methods particularly adapted for body fluid sampling |
US4986671A (en) * | 1989-04-12 | 1991-01-22 | Luxtron Corporation | Three-parameter optical fiber sensor and system |
US4953552A (en) | 1989-04-21 | 1990-09-04 | Demarzo Arthur P | Blood glucose monitoring system |
EP0396788A1 (en) | 1989-05-08 | 1990-11-14 | Dräger Nederland B.V. | Process and sensor for measuring the glucose content of glucosecontaining fluids |
US5034461A (en) | 1989-06-07 | 1991-07-23 | Bausch & Lomb Incorporated | Novel prepolymers useful in biomedical devices |
CH677149A5 (en) | 1989-07-07 | 1991-04-15 | Disetronic Ag | |
US4979509A (en) | 1989-07-19 | 1990-12-25 | Northstar Research Institute, Ltd. | Continuous glucose monitoring and a system utilized therefor |
US5264104A (en) | 1989-08-02 | 1993-11-23 | Gregg Brian A | Enzyme electrodes |
FR2650756B1 (en) | 1989-08-11 | 1991-10-31 | Inst Francais Du Petrole | GAS SEPARATION MEMBRANE |
US5041092A (en) | 1989-08-29 | 1991-08-20 | Medical Engineering Corporation | Urethral indwelling catheter with magnetically controlled drainage valve and method |
US5050612A (en) | 1989-09-12 | 1991-09-24 | Matsumura Kenneth N | Device for computer-assisted monitoring of the body |
US5002590A (en) | 1989-09-19 | 1991-03-26 | Bend Research, Inc. | Countercurrent dehydration by hollow fibers |
FR2652736A1 (en) | 1989-10-06 | 1991-04-12 | Neftel Frederic | IMPLANTABLE DEVICE FOR EVALUATING THE RATE OF GLUCOSE. |
JPH03133440A (en) | 1989-10-18 | 1991-06-06 | Nishitomo:Kk | Clinical thermometer for ladies |
IT1251509B (en) | 1989-11-24 | 1995-05-16 | Leonardo Cammilli | IMPLANTABLE DEFIBRILLATOR WITH AUTOMATIC RECOGNITION OF VENTRICULAR FIBRILLATION, WITH PHARMACOLOGICAL ACTION |
US5067491A (en) | 1989-12-08 | 1991-11-26 | Becton, Dickinson And Company | Barrier coating on blood contacting devices |
US5030199A (en) | 1989-12-11 | 1991-07-09 | Medical Engineering Corporation | Female incontinence control device with magnetically operable valve and method |
US5342789A (en) | 1989-12-14 | 1994-08-30 | Sensor Technologies, Inc. | Method and device for detecting and quantifying glucose in body fluids |
US5985129A (en) | 1989-12-14 | 1999-11-16 | The Regents Of The University Of California | Method for increasing the service life of an implantable sensor |
US5183549A (en) * | 1990-01-26 | 1993-02-02 | Commtech International Management Corporation | Multi-analyte sensing electrolytic cell |
US5109850A (en) | 1990-02-09 | 1992-05-05 | Massachusetts Institute Of Technology | Automatic blood monitoring for medication delivery method and apparatus |
US5055198A (en) | 1990-03-07 | 1991-10-08 | Shettigar U Ramakrishna | Autologous blood recovery membrane system and method |
US5316008A (en) | 1990-04-06 | 1994-05-31 | Casio Computer Co., Ltd. | Measurement of electrocardiographic wave and sphygmus |
US5165407A (en) | 1990-04-19 | 1992-11-24 | The University Of Kansas | Implantable glucose sensor |
US5713926A (en) | 1990-04-25 | 1998-02-03 | Cardiac Pacemakers, Inc. | Implantable intravenous cardiac stimulation system with pulse generator housing serving as optional additional electrode |
GB9009409D0 (en) | 1990-04-26 | 1990-06-20 | Dow Corning | Film-forming copolymers and their use in water vapour permeable coatings |
US5331555A (en) | 1990-05-11 | 1994-07-19 | Sharp Kabushiki Kaisha | Electronic apparatus |
IT1248934B (en) | 1990-06-01 | 1995-02-11 | Fidia Spa | BIOCOMPATIBLE PERFORATED MEMBRANES, PROCESSES FOR THEIR PREPARATION, THEIR USE AS A SUPPORT FOR THE IN VITRO GROWTH OF EPITHELIAL CELLS, ARTIFICIAL LEATHER THUS OBTAINED AND THEIR USE IN LEATHER TRANSPLANTS |
US5147725A (en) | 1990-07-03 | 1992-09-15 | Corvita Corporation | Method for bonding silicone rubber and polyurethane materials and articles manufactured thereby |
US5202261A (en) | 1990-07-19 | 1993-04-13 | Miles Inc. | Conductive sensors and their use in diagnostic assays |
US5250439A (en) | 1990-07-19 | 1993-10-05 | Miles Inc. | Use of conductive sensors in diagnostic assays |
US5746898A (en) | 1990-08-10 | 1998-05-05 | Siemens Aktiengesellschaft | Electrochemical-enzymatic sensor |
CA2090435C (en) * | 1990-08-28 | 2000-12-12 | Peter J. Schmitt | Self-supporting woven vascular graft |
JP2701977B2 (en) | 1990-09-28 | 1998-01-21 | ファイザー インク | Dosage form containing hydrophobic medium |
US5733336A (en) | 1990-10-31 | 1998-03-31 | Baxter International, Inc. | Ported tissue implant systems and methods of using same |
KR0169495B1 (en) | 1990-10-31 | 1999-01-15 | 쥐. 마샬 애비 | Close vascularization implant material |
US5314471A (en) * | 1991-07-24 | 1994-05-24 | Baxter International Inc. | Tissue inplant systems and methods for sustaining viable high cell densities within a host |
US5344454A (en) | 1991-07-24 | 1994-09-06 | Baxter International Inc. | Closed porous chambers for implanting tissue in a host |
US5713888A (en) * | 1990-10-31 | 1998-02-03 | Baxter International, Inc. | Tissue implant systems |
DE69228957T2 (en) | 1991-01-16 | 1999-10-07 | Toyo Boseki K.K., Osaka | Blood compatible material |
AU1356792A (en) | 1991-01-25 | 1992-08-27 | Markwell Medical Institute, Inc. | Implantable biological fluid measuring device |
US5348788A (en) | 1991-01-30 | 1994-09-20 | Interpore Orthopaedics, Inc. | Mesh sheet with microscopic projections and holes |
AU1579092A (en) | 1991-02-27 | 1992-10-06 | Nova Pharmaceutical Corporation | Anti-infective and anti-inflammatory releasing systems for medical devices |
US5593852A (en) * | 1993-12-02 | 1997-01-14 | Heller; Adam | Subcutaneous glucose electrode |
US5773270A (en) | 1991-03-12 | 1998-06-30 | Chiron Diagnostics Corporation | Three-layered membrane for use in an electrochemical sensor system |
US5397848A (en) | 1991-04-25 | 1995-03-14 | Allergan, Inc. | Enhancing the hydrophilicity of silicone polymers |
SG47470A1 (en) | 1991-04-25 | 1998-04-17 | Univ Brown Res Found | Implantable biocompatible immunoisolatory vehicle for delivery of a selected therapeutic products |
JPH08196626A (en) | 1991-04-25 | 1996-08-06 | Toyobo Co Ltd | Blood compatible artificial pulmonary membrane |
US5391164A (en) | 1991-05-03 | 1995-02-21 | Giampapa; Vincent C. | Subcutaneous implantable multiple-agent delivery system |
US5271736A (en) | 1991-05-13 | 1993-12-21 | Applied Medical Research | Collagen disruptive morphology for implants |
JP3084642B2 (en) | 1991-05-30 | 2000-09-04 | 株式会社ジェルテック | Pad for dressing and method of manufacturing the same |
US5112301A (en) | 1991-06-19 | 1992-05-12 | Strato Medical Corporation | Bidirectional check valve catheter |
US5453278A (en) | 1991-07-24 | 1995-09-26 | Baxter International Inc. | Laminated barriers for tissue implants |
WO1993006116A1 (en) * | 1991-09-20 | 1993-04-01 | Syntex-Synergen Neuroscience Joint Venture | Glial derived neurotrophic factor |
US5322063A (en) | 1991-10-04 | 1994-06-21 | Eli Lilly And Company | Hydrophilic polyurethane membranes for electrochemical glucose sensors |
US5155149A (en) | 1991-10-10 | 1992-10-13 | Boc Health Care, Inc. | Silicone polyurethane copolymers containing oxygen sensitive phosphorescent dye compounds |
US5681572A (en) | 1991-10-18 | 1997-10-28 | Seare, Jr.; William J. | Porous material product and process |
US5249576A (en) | 1991-10-24 | 1993-10-05 | Boc Health Care, Inc. | Universal pulse oximeter probe |
EP0539625A1 (en) | 1991-10-28 | 1993-05-05 | Dräger Medical Electronics B.V. | Electrochemical sensor for measuring the glucose content of glucose containing fluids |
KR100273834B1 (en) * | 1991-12-18 | 2000-12-15 | 아놀드 데이비드 씨. | Medical valve |
WO1993013408A1 (en) | 1991-12-31 | 1993-07-08 | Abbott Laboratories | Composite membrane |
US5296144A (en) | 1992-01-02 | 1994-03-22 | World Trade Corporation | Composite membrane of a hydrophilic asymmetric membrane coated with an organosiloxane block copolymer |
US5217594A (en) | 1992-01-15 | 1993-06-08 | Enzyme Technology Research Group, Inc. | Convenient determination of trace lead in whole blood and other fluids |
AU669350B2 (en) | 1992-02-01 | 1996-06-06 | Victoria University Of Manchester, The | Electrode |
NL9200207A (en) | 1992-02-05 | 1993-09-01 | Nedap Nv | IMPLANTABLE BIOMEDICAL SENSOR DEVICE, IN PARTICULAR FOR MEASUREMENT OF THE GLUCOSE CONCENTRATION. |
US5284140A (en) | 1992-02-11 | 1994-02-08 | Eli Lilly And Company | Acrylic copolymer membranes for biosensors |
US5453248A (en) | 1992-03-09 | 1995-09-26 | Optical Sensors Incorporated | Cross-linked gas permeable membrane of a cured perfluorinated urethane polymer, and optical gas sensors fabricated therewith |
US5423738A (en) | 1992-03-13 | 1995-06-13 | Robinson; Thomas C. | Blood pumping and processing system |
JPH05279447A (en) | 1992-03-31 | 1993-10-26 | Mitsubishi Rayon Co Ltd | Silicon-based block copolymer and membrane made thereof |
PT676935E (en) | 1992-04-01 | 2002-04-29 | Baxter Int | ANGIOGENIC FABRIC IMPLANT SYSTEMS |
JPH0650792A (en) | 1992-04-15 | 1994-02-25 | Fisher & Paykel Ltd | Apparatus and method for controlling liquid supply |
US5589563A (en) | 1992-04-24 | 1996-12-31 | The Polymer Technology Group | Surface-modifying endgroups for biomedical polymers |
DE69320470T2 (en) | 1992-04-24 | 1999-04-29 | The Polymer Technology Group, Inc., Emeryville, Calif. | COPOLYMERS AND NON-POROUS SEMI-PLEASANT MEMBRANES MADE THEREOF AND THEIR USE FOR FILTERING MOLECULES IN A PRESET MOLECULAR WEIGHT RANGE |
US5316452A (en) | 1992-05-11 | 1994-05-31 | Gilbert Corporation | Dispensing assembly with interchangeable cartridge pumps |
GB9211402D0 (en) | 1992-05-29 | 1992-07-15 | Univ Manchester | Sensor devices |
US5344451A (en) | 1992-06-24 | 1994-09-06 | Dayton Michael P | Synthetic reconstructive implant device |
US5330521A (en) | 1992-06-29 | 1994-07-19 | Cohen Donald M | Low resistance implantable electrical leads |
US5208313A (en) | 1992-07-16 | 1993-05-04 | Surface Coatings, Inc. | Waterproof breathable polyurethane membranes and porous substrates protected therewith |
US5676651A (en) | 1992-08-06 | 1997-10-14 | Electric Boat Corporation | Surgically implantable pump arrangement and method for pumping body fluids |
US5330634A (en) | 1992-08-28 | 1994-07-19 | Via Medical Corporation | Calibration solutions useful for analyses of biological fluids and methods employing same |
JP2541081B2 (en) * | 1992-08-28 | 1996-10-09 | 日本電気株式会社 | Biosensor and method of manufacturing and using biosensor |
CA2145996A1 (en) | 1992-10-01 | 1994-04-14 | Burkhard Raguse | Improved sensor membranes |
GB9221099D0 (en) | 1992-10-07 | 1992-11-18 | Ecossensors Ltd | Improvements in and relating to gas permeable membranes for amperometric gas electrodes |
US5387327A (en) * | 1992-10-19 | 1995-02-07 | Duquesne University Of The Holy Ghost | Implantable non-enzymatic electrochemical glucose sensor |
US6256522B1 (en) | 1992-11-23 | 2001-07-03 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Sensors for continuous monitoring of biochemicals and related method |
US5626563A (en) | 1993-01-12 | 1997-05-06 | Minnesota Mining And Manufacturing Company | Irrigation system with tubing cassette |
US5587273A (en) | 1993-01-21 | 1996-12-24 | Advanced Microbotics Corporation | Molecularly imprinted materials, method for their preparation and devices employing such materials |
US5299571A (en) | 1993-01-22 | 1994-04-05 | Eli Lilly And Company | Apparatus and method for implantation of sensors |
US5389430A (en) | 1993-02-05 | 1995-02-14 | Th. Goldschmidt Ag | Textiles coated with waterproof, moisture vapor permeable polymers |
WO1994022367A1 (en) | 1993-03-30 | 1994-10-13 | Pfizer Inc. | Radiotelemetry impedance plethysmography device |
US5411866A (en) | 1993-03-30 | 1995-05-02 | National Research Council Of Canada | Method and system for determining bioactive substances |
US5387329A (en) * | 1993-04-09 | 1995-02-07 | Ciba Corning Diagnostics Corp. | Extended use planar sensors |
AU692786B2 (en) | 1993-07-02 | 1998-06-18 | Materials Evolution And Development Usa, Inc. | Implantable system for cell growth control |
CA2127817C (en) | 1993-07-13 | 2007-07-03 | Hitoshi Tsugaya | Tobacco filters and method of producing the same |
DE4329898A1 (en) | 1993-09-04 | 1995-04-06 | Marcus Dr Besson | Wireless medical diagnostic and monitoring device |
US5582184A (en) | 1993-10-13 | 1996-12-10 | Integ Incorporated | Interstitial fluid collection and constituent measurement |
US5545220A (en) | 1993-11-04 | 1996-08-13 | Lipomatrix Incorporated | Implantable prosthesis with open cell textured surface and method for forming same |
US5497772A (en) | 1993-11-19 | 1996-03-12 | Alfred E. Mann Foundation For Scientific Research | Glucose monitoring system |
US5791344A (en) | 1993-11-19 | 1998-08-11 | Alfred E. Mann Foundation For Scientific Research | Patient monitoring system |
US5443080A (en) | 1993-12-22 | 1995-08-22 | Americate Transtech, Inc. | Integrated system for biological fluid constituent analysis |
US5437824A (en) | 1993-12-23 | 1995-08-01 | Moghan Medical Corp. | Method of forming a molded silicone foam implant having open-celled interstices |
US5549675A (en) | 1994-01-11 | 1996-08-27 | Baxter International, Inc. | Method for implanting tissue in a host |
DE4401400A1 (en) | 1994-01-19 | 1995-07-20 | Ernst Prof Dr Pfeiffer | Method and arrangement for continuously monitoring the concentration of a metabolite |
US6127154A (en) | 1994-02-10 | 2000-10-03 | Mosbach; Klaus | Methods for direct synthesis of compounds having complementary structure to a desired molecular entity and use thereof |
US5549651A (en) | 1994-05-25 | 1996-08-27 | Lynn; Lawrence A. | Luer-receiving medical valve and fluid transfer method |
US5482446A (en) | 1994-03-09 | 1996-01-09 | Baxter International Inc. | Ambulatory infusion pump |
US5531679A (en) | 1994-03-14 | 1996-07-02 | Schulman; Joseph H. | Fluidic infusion system for catheter or probe |
US5390671A (en) * | 1994-03-15 | 1995-02-21 | Minimed Inc. | Transcutaneous sensor insertion set |
US5505713A (en) | 1994-04-01 | 1996-04-09 | Minimed Inc. | Indwelling catheter with stable enzyme coating |
US5584876A (en) | 1994-04-29 | 1996-12-17 | W. L. Gore & Associates, Inc. | Cell excluding sheath for vascular grafts |
DE4415896A1 (en) | 1994-05-05 | 1995-11-09 | Boehringer Mannheim Gmbh | Analysis system for monitoring the concentration of an analyte in the blood of a patient |
US5484404A (en) * | 1994-05-06 | 1996-01-16 | Alfred E. Mann Foundation For Scientific Research | Replaceable catheter system for physiological sensors, tissue stimulating electrodes and/or implantable fluid delivery systems |
US5651767A (en) | 1994-05-06 | 1997-07-29 | Alfred F. Mann Foundation For Scientific Research | Replaceable catheter system for physiological sensors, stimulating electrodes and/or implantable fluid delivery systems |
US5482473A (en) * | 1994-05-09 | 1996-01-09 | Minimed Inc. | Flex circuit connector |
US5766839A (en) | 1994-06-17 | 1998-06-16 | Ysi Incorporated | Processes for preparing barrier layer films for use in enzyme electrodes and films made thereby |
DE4422068A1 (en) * | 1994-06-23 | 1996-01-04 | Siemens Ag | Electro-catalytic glucose sensor in catheter form |
US5494562A (en) * | 1994-06-27 | 1996-02-27 | Ciba Corning Diagnostics Corp. | Electrochemical sensors |
DE69505391T2 (en) | 1994-07-08 | 1999-06-17 | Baxter International Inc., Deerfield, Ill. 60015 | IMPLANTED TUMOR CELL TREATMENT FOR CANCER |
US5514253A (en) | 1994-07-13 | 1996-05-07 | I-Stat Corporation | Method of measuring gas concentrations and microfabricated sensing device for practicing same |
US5605152A (en) * | 1994-07-18 | 1997-02-25 | Minimed Inc. | Optical glucose sensor |
US6007845A (en) | 1994-07-22 | 1999-12-28 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US5509888A (en) | 1994-07-26 | 1996-04-23 | Conceptek Corporation | Controller valve device and method |
US5591453A (en) | 1994-07-27 | 1997-01-07 | The Trustees Of The University Of Pennsylvania | Incorporation of biologically active molecules into bioactive glasses |
US5513636A (en) | 1994-08-12 | 1996-05-07 | Cb-Carmel Biotechnology Ltd. | Implantable sensor chip |
US5462051A (en) | 1994-08-31 | 1995-10-31 | Colin Corporation | Medical communication system |
US5569219A (en) | 1994-09-13 | 1996-10-29 | Hakki; A-Hamid | Collapsible catheter |
AT402452B (en) | 1994-09-14 | 1997-05-26 | Avl Verbrennungskraft Messtech | PLANAR SENSOR FOR DETECTING A CHEMICAL PARAMETER OF A SAMPLE |
US5624537A (en) | 1994-09-20 | 1997-04-29 | The University Of British Columbia - University-Industry Liaison Office | Biosensor and interface membrane |
US5840026A (en) | 1994-09-21 | 1998-11-24 | Medrad, Inc. | Patient specific dosing contrast delivery systems and methods |
US5807406A (en) | 1994-10-07 | 1998-09-15 | Baxter International Inc. | Porous microfabricated polymer membrane structures |
US5552112A (en) | 1995-01-26 | 1996-09-03 | Quiclave, Llc | Method and system for sterilizing medical instruments |
CA2202511A1 (en) | 1994-10-12 | 1996-04-25 | Laurence A. Roth | Targeted delivery via biodegradable polymers |
US6045671A (en) | 1994-10-18 | 2000-04-04 | Symyx Technologies, Inc. | Systems and methods for the combinatorial synthesis of novel materials |
CA2159052C (en) | 1994-10-28 | 2007-03-06 | Rainer Alex | Injection device |
IE72524B1 (en) | 1994-11-04 | 1997-04-23 | Elan Med Tech | Analyte-controlled liquid delivery device and analyte monitor |
ES2173979T3 (en) * | 1994-11-14 | 2002-11-01 | Bayer Ag | THERMOPLASTIC POLYURETHANES SEGMENTED RANDOMLY AS A MATRIX FOR THE ELECTROCHEMICAL ANALYSIS OF IONS CA ++. |
US6281015B1 (en) | 1994-12-16 | 2001-08-28 | Children's Medical Center Corp. | Localized delivery of factors enhancing survival of transplanted cells |
US5520788A (en) | 1995-01-17 | 1996-05-28 | The Yellow Springs Instrument Company, Inc. | Support layer for enzyme electrode laminated membranes |
US5586553A (en) | 1995-02-16 | 1996-12-24 | Minimed Inc. | Transcutaneous sensor insertion set |
US5568806A (en) | 1995-02-16 | 1996-10-29 | Minimed Inc. | Transcutaneous sensor insertion set |
US5628619A (en) | 1995-03-06 | 1997-05-13 | Sabratek Corporation | Infusion pump having power-saving modes |
EP2280268B1 (en) | 1995-03-10 | 2014-09-03 | Meso Scale Technologies, LLC. | Multi-array, multi-specific electrochemiluminescence testing |
US5640470A (en) | 1995-03-27 | 1997-06-17 | Abbott Laboratories | Fiber-optic detectors with terpolymeric analyte-permeable matrix coating |
US5786439A (en) | 1996-10-24 | 1998-07-28 | Minimed Inc. | Hydrophilic, swellable coatings for biosensors |
US5882494A (en) * | 1995-03-27 | 1999-03-16 | Minimed, Inc. | Polyurethane/polyurea compositions containing silicone for biosensor membranes |
DE29624309U1 (en) | 1995-04-04 | 2002-01-03 | Commonwealth Scientific And Industrial Research Organisation, Campbell | Duration supporting lenses |
WO1996032076A1 (en) | 1995-04-11 | 1996-10-17 | Baxter Internatonal Inc. | Tissue implant systems |
US6656157B1 (en) | 1995-04-20 | 2003-12-02 | Acist Medical Systems, Inc. | Infinitely refillable syringe |
GB9509410D0 (en) | 1995-05-10 | 1995-07-05 | Imperial College | Molecular imaging |
US6060640A (en) | 1995-05-19 | 2000-05-09 | Baxter International Inc. | Multiple-layer, formed-in-place immunoisolation membrane structures for implantation of cells in host tissue |
US5626561A (en) | 1995-06-07 | 1997-05-06 | Gore Hybrid Technologies, Inc. | Implantable containment apparatus for a therapeutical device and method for loading and reloading the device therein |
US5609629A (en) | 1995-06-07 | 1997-03-11 | Med Institute, Inc. | Coated implantable medical device |
US5743262A (en) | 1995-06-07 | 1998-04-28 | Masimo Corporation | Blood glucose monitoring system |
EP0773753B1 (en) | 1995-06-07 | 2003-10-08 | Gore Hybrid Technologies, Inc. | An implantable containment apparatus for a therapeutical device |
US5630978A (en) * | 1995-06-07 | 1997-05-20 | Yissum Research Development Co. Of The Hebrew University Of Jerusalem | Preparation of biologically active molecules by molecular imprinting |
US5637135A (en) | 1995-06-26 | 1997-06-10 | Capillary Technology Corporation | Chromatographic stationary phases and adsorbents from hybrid organic-inorganic sol-gels |
US5995860A (en) | 1995-07-06 | 1999-11-30 | Thomas Jefferson University | Implantable sensor and system for measurement and control of blood constituent levels |
US6183437B1 (en) * | 1995-07-10 | 2001-02-06 | Frank J. Walker | Electronic control unit and tubing assembly system for automatically controlling urinary irrigation |
US5688239A (en) | 1995-07-10 | 1997-11-18 | Walker; Frank J. | Urinary tract treating assembly with prostate flushing |
US5611900A (en) | 1995-07-20 | 1997-03-18 | Michigan State University | Microbiosensor used in-situ |
US5700902A (en) | 1995-07-27 | 1997-12-23 | Circe Biomedical, Inc. | Block copolymers |
US5673694A (en) | 1995-08-08 | 1997-10-07 | Henry Ford Health System | Method and apparatus for continuous measurement of central venous oxygen saturation |
US6001471A (en) | 1995-08-11 | 1999-12-14 | 3M Innovative Properties Company | Removable adhesive tape with controlled sequential release |
CA2229743A1 (en) | 1995-09-21 | 1997-03-27 | Novartis Ag | Polymer-bound fluorophores as optical ion sensors |
CA2232588A1 (en) | 1995-09-26 | 1997-04-03 | Ameron International Corporation | Polysiloxane polyurethane compositions |
US5628890A (en) | 1995-09-27 | 1997-05-13 | Medisense, Inc. | Electrochemical sensor |
US5665222A (en) | 1995-10-11 | 1997-09-09 | E. Heller & Company | Soybean peroxidase electrochemical sensor |
US5972199A (en) | 1995-10-11 | 1999-10-26 | E. Heller & Company | Electrochemical analyte sensors using thermostable peroxidase |
US6689265B2 (en) * | 1995-10-11 | 2004-02-10 | Therasense, Inc. | Electrochemical analyte sensors using thermostable soybean peroxidase |
US5855613A (en) | 1995-10-13 | 1999-01-05 | Islet Sheet Medical, Inc. | Retrievable bioartificial implants having dimensions allowing rapid diffusion of oxygen and rapid biological response to physiological change |
DE69620011D1 (en) | 1995-10-16 | 2002-04-25 | Procter & Gamble | CONDITIONING SHAMPOO COMPOSITIONS WITH IMPROVED STABILITY |
CN1086939C (en) | 1995-10-16 | 2002-07-03 | 普罗克特和甘保尔公司 | Conditioning shampoos containing polyalkylene glycol |
JP2000500656A (en) * | 1995-11-22 | 2000-01-25 | ミニメッド インコーポレイティド | Detection of biomolecules using chemical amplification and optical sensors |
US5711861A (en) | 1995-11-22 | 1998-01-27 | Ward; W. Kenneth | Device for monitoring changes in analyte concentration |
US6002954A (en) | 1995-11-22 | 1999-12-14 | The Regents Of The University Of California | Detection of biological molecules using boronate-based chemical amplification and optical sensors |
US6063637A (en) | 1995-12-13 | 2000-05-16 | California Institute Of Technology | Sensors for sugars and other metal binding analytes |
DE69637553D1 (en) * | 1995-12-19 | 2008-07-10 | Abbott Lab | Device for detecting an analyte and administering a therapeutic substance |
DE69623647T2 (en) | 1995-12-22 | 2003-05-28 | Novartis Ag, Basel | POLYURETHANE MADE OF POLYSILOXANE-POLYOL MACROMER |
US5637083A (en) | 1996-01-19 | 1997-06-10 | Pudenz-Schulte Medical Research Corporation | Implantable adjustable fluid flow control valve |
US5795453A (en) | 1996-01-23 | 1998-08-18 | Gilmartin; Markas A. T. | Electrodes and metallo isoindole ringed compounds |
AU2260397A (en) | 1996-01-31 | 1997-08-22 | Trustees Of The University Of Pennsylvania, The | Remote control drug delivery device |
US5833603A (en) | 1996-03-13 | 1998-11-10 | Lipomatrix, Inc. | Implantable biosensing transponder |
US6407195B2 (en) | 1996-04-25 | 2002-06-18 | 3M Innovative Properties Company | Tackified polydiorganosiloxane oligourea segmented copolymers and a process for making same |
US5820589A (en) | 1996-04-30 | 1998-10-13 | Medtronic, Inc. | Implantable non-invasive rate-adjustable pump |
US6048691A (en) | 1996-05-13 | 2000-04-11 | Motorola, Inc. | Method and system for performing a binding assay |
US6022463A (en) * | 1996-05-16 | 2000-02-08 | Sendx Medical, Inc. | Sensors with subminiature through holes |
US5776324A (en) | 1996-05-17 | 1998-07-07 | Encelle, Inc. | Electrochemical biosensors |
US5964261A (en) | 1996-05-29 | 1999-10-12 | Baxter International Inc. | Implantation assembly |
JP2943700B2 (en) | 1996-07-10 | 1999-08-30 | 日本電気株式会社 | Biosensor |
WO1998002209A2 (en) | 1996-07-11 | 1998-01-22 | Medtronic, Inc. | Minimally invasive implantable device for monitoring physiologic events |
US6325978B1 (en) | 1998-08-04 | 2001-12-04 | Ntc Technology Inc. | Oxygen monitoring and apparatus |
US5703359A (en) | 1996-07-29 | 1997-12-30 | Leybold Inficon, Inc. | Composite membrane and support assembly |
US6054142A (en) | 1996-08-01 | 2000-04-25 | Cyto Therapeutics, Inc. | Biocompatible devices with foam scaffolds |
US5804048A (en) | 1996-08-15 | 1998-09-08 | Via Medical Corporation | Electrode assembly for assaying glucose |
US6018013A (en) * | 1996-09-03 | 2000-01-25 | Nkk Corporation | Coating composition and method for producing precoated steel sheets |
US5836887A (en) | 1996-09-19 | 1998-11-17 | Colin Corporation | Physical information monitor system having means for determining reference range for abnormality determination, based on moving average of previously obtained values |
US5932175A (en) | 1996-09-25 | 1999-08-03 | Via Medical Corporation | Sensor apparatus for use in measuring a parameter of a fluid sample |
DE19642453C2 (en) | 1996-10-15 | 1998-07-23 | Bosch Gmbh Robert | Arrangement for gas sensor electrodes |
US6001068A (en) | 1996-10-22 | 1999-12-14 | Terumo Kabushiki Kaisha | Guide wire having tubular connector with helical slits |
US6071406A (en) | 1996-11-12 | 2000-06-06 | Whatman, Inc. | Hydrophilic polymeric phase inversion membrane |
EP0944731B1 (en) | 1996-11-14 | 2006-01-18 | Radiometer Medical ApS | Enzyme sensor |
US5811487A (en) | 1996-12-16 | 1998-09-22 | Dow Corning Corporation | Thickening silicones with elastomeric silicone polyethers |
US5964993A (en) | 1996-12-19 | 1999-10-12 | Implanted Biosystems Inc. | Glucose sensor |
US5914026A (en) | 1997-01-06 | 1999-06-22 | Implanted Biosystems Inc. | Implantable sensor employing an auxiliary electrode |
US6213739B1 (en) | 1997-01-17 | 2001-04-10 | Niagara Pump Corporation | Linear peristaltic pump |
WO1998032013A1 (en) | 1997-01-17 | 1998-07-23 | Via Medical Corporation | Method for calibrating sensors used in diagnostic testing |
US5928155A (en) | 1997-01-24 | 1999-07-27 | Cardiox Corporation | Cardiac output measurement with metabolizable analyte containing fluid |
US6607509B2 (en) | 1997-12-31 | 2003-08-19 | Medtronic Minimed, Inc. | Insertion device for an insertion set and method of using the same |
US6093172A (en) | 1997-02-05 | 2000-07-25 | Minimed Inc. | Injector for a subcutaneous insertion set |
US6891317B2 (en) * | 2001-05-22 | 2005-05-10 | Sri International | Rolled electroactive polymers |
US7192450B2 (en) | 2003-05-21 | 2007-03-20 | Dexcom, Inc. | Porous membranes for use with implantable devices |
US20050033132A1 (en) | 1997-03-04 | 2005-02-10 | Shults Mark C. | Analyte measuring device |
US7899511B2 (en) | 2004-07-13 | 2011-03-01 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US6741877B1 (en) | 1997-03-04 | 2004-05-25 | Dexcom, Inc. | Device and method for determining analyte levels |
US6862465B2 (en) * | 1997-03-04 | 2005-03-01 | Dexcom, Inc. | Device and method for determining analyte levels |
US6558321B1 (en) | 1997-03-04 | 2003-05-06 | Dexcom, Inc. | Systems and methods for remote monitoring and modulation of medical devices |
US7657297B2 (en) | 2004-05-03 | 2010-02-02 | Dexcom, Inc. | Implantable analyte sensor |
US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
US5961451A (en) | 1997-04-07 | 1999-10-05 | Motorola, Inc. | Noninvasive apparatus having a retaining member to retain a removable biosensor |
US6059946A (en) | 1997-04-14 | 2000-05-09 | Matsushita Electric Industrial Co., Ltd. | Biosensor |
AT404992B (en) | 1997-04-17 | 1999-04-26 | Avl List Gmbh | SENSOR FOR DETERMINING AN ENZYME SUBSTRATE |
US5935785A (en) | 1997-04-30 | 1999-08-10 | Motorola, Inc. | Binding assay methods |
US6018033A (en) * | 1997-05-13 | 2000-01-25 | Purdue Research Foundation | Hydrophilic, hydrophobic, and thermoreversible saccharide gels and forms, and methods for producing same |
US6558351B1 (en) | 1999-06-03 | 2003-05-06 | Medtronic Minimed, Inc. | Closed loop system for controlling insulin infusion |
US5954643A (en) | 1997-06-09 | 1999-09-21 | Minimid Inc. | Insertion set for a transcutaneous sensor |
ATE498838T1 (en) * | 1997-06-12 | 2011-03-15 | Clinical Micro Sensors Inc | ELECTRONIC METHOD AND DEVICE FOR DETECTING ANALYTES |
JP2002505008A (en) | 1997-06-16 | 2002-02-12 | エラン コーポレーション ピーエルシー | Methods for calibrating and testing sensors for in vivo measurement of analytes and devices for use in such methods |
US6013711A (en) | 1997-06-18 | 2000-01-11 | Ck Witco Corporation | Hydrophilic polysiloxane compositions |
US5928182A (en) | 1997-07-02 | 1999-07-27 | Johnson & Johnson Professional, Inc. | Pediatric programmable hydrocephalus valve |
US5871514A (en) | 1997-08-01 | 1999-02-16 | Medtronic, Inc. | Attachment apparatus for an implantable medical device employing ultrasonic energy |
GB9717906D0 (en) | 1997-08-23 | 1997-10-29 | Univ Manchester | Sensor Devices And Analytical Methods |
US6051372A (en) | 1997-09-09 | 2000-04-18 | Nimbus Biotechnologie Gmbh | Template induced patterning of surfaces and their reversible stabilization using phase transitions of the patterned material |
US5917346A (en) | 1997-09-12 | 1999-06-29 | Alfred E. Mann Foundation | Low power current to frequency converter circuit for use in implantable sensors |
US5999848A (en) | 1997-09-12 | 1999-12-07 | Alfred E. Mann Foundation | Daisy chainable sensors and stimulators for implantation in living tissue |
US6259937B1 (en) | 1997-09-12 | 2001-07-10 | Alfred E. Mann Foundation | Implantable substrate sensor |
US6033366A (en) | 1997-10-14 | 2000-03-07 | Data Sciences International, Inc. | Pressure measurement device |
US6585763B1 (en) | 1997-10-14 | 2003-07-01 | Vascusense, Inc. | Implantable therapeutic device and method |
US6088608A (en) | 1997-10-20 | 2000-07-11 | Alfred E. Mann Foundation | Electrochemical sensor and integrity tests therefor |
US6081736A (en) | 1997-10-20 | 2000-06-27 | Alfred E. Mann Foundation | Implantable enzyme-based monitoring systems adapted for long term use |
US6119028A (en) | 1997-10-20 | 2000-09-12 | Alfred E. Mann Foundation | Implantable enzyme-based monitoring systems having improved longevity due to improved exterior surfaces |
US6319566B1 (en) | 1997-11-12 | 2001-11-20 | John C. Polanyi | Method of molecular-scale pattern imprinting at surfaces |
US6117643A (en) * | 1997-11-25 | 2000-09-12 | Ut Battelle, Llc | Bioluminescent bioreporter integrated circuit |
US6579690B1 (en) | 1997-12-05 | 2003-06-17 | Therasense, Inc. | Blood analyte monitoring through subcutaneous measurement |
US6893552B1 (en) | 1997-12-29 | 2005-05-17 | Arrowhead Center, Inc. | Microsensors for glucose and insulin monitoring |
WO1999033504A1 (en) | 1997-12-31 | 1999-07-08 | Minimed Inc. | Insertion device for an insertion set and method of using the same |
US7066884B2 (en) | 1998-01-08 | 2006-06-27 | Sontra Medical, Inc. | System, method, and device for non-invasive body fluid sampling and analysis |
US6030827A (en) | 1998-01-23 | 2000-02-29 | I-Stat Corporation | Microfabricated aperture-based sensor |
DE69907427T2 (en) | 1998-02-02 | 2004-03-18 | Medtronic, Inc., Minneapolis | IMPLANTABLE INFUSION DEVICE WITH A SAFETY VALVE |
US7070577B1 (en) | 1998-02-02 | 2006-07-04 | Medtronic, Inc | Drive circuit having improved energy efficiency for implantable beneficial agent infusion or delivery device |
US6103033A (en) | 1998-03-04 | 2000-08-15 | Therasense, Inc. | Process for producing an electrochemical biosensor |
US6134461A (en) | 1998-03-04 | 2000-10-17 | E. Heller & Company | Electrochemical analyte |
US6299583B1 (en) | 1998-03-17 | 2001-10-09 | Cardiox Corporation | Monitoring total circulating blood volume and cardiac output |
GB9805896D0 (en) | 1998-03-20 | 1998-05-13 | Eglise David | Remote analysis system |
US6091975A (en) | 1998-04-01 | 2000-07-18 | Alza Corporation | Minimally invasive detecting device |
US6537318B1 (en) | 1998-04-06 | 2003-03-25 | Konjac Technologies, Llc | Use of glucomannan hydrocolloid as filler material in prostheses |
US6223080B1 (en) | 1998-04-29 | 2001-04-24 | Medtronic, Inc. | Power consumption reduction in medical devices employing multiple digital signal processors and different supply voltages |
US6175752B1 (en) * | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6949816B2 (en) | 2003-04-21 | 2005-09-27 | Motorola, Inc. | Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same |
PT1077636E (en) | 1998-05-13 | 2004-06-30 | Cygnus Therapeutic Systems | SIGNAL PROCESSING FOR PHYSIOLOGICAL ANALYZES MEDICATION |
US6526298B1 (en) * | 1998-05-18 | 2003-02-25 | Abbott Laboratories | Method for the non-invasive determination of analytes in a selected volume of tissue |
US6129757A (en) | 1998-05-18 | 2000-10-10 | Scimed Life Systems | Implantable members for receiving therapeutically useful compositions |
US7540875B2 (en) * | 1998-06-01 | 2009-06-02 | Avatar Design & Development, Inc. | Surgical cutting tool with automatically retractable blade assembly |
US6294281B1 (en) | 1998-06-17 | 2001-09-25 | Therasense, Inc. | Biological fuel cell and method |
US6077299A (en) | 1998-06-22 | 2000-06-20 | Eyetronic, Llc | Non-invasively adjustable valve implant for the drainage of aqueous humor in glaucoma |
US6761816B1 (en) * | 1998-06-23 | 2004-07-13 | Clinical Micro Systems, Inc. | Printed circuit boards with monolayers and capture ligands |
US6290839B1 (en) | 1998-06-23 | 2001-09-18 | Clinical Micro Sensors, Inc. | Systems for electrophoretic transport and detection of analytes |
US6272382B1 (en) | 1998-07-31 | 2001-08-07 | Advanced Bionics Corporation | Fully implantable cochlear implant system |
US6248067B1 (en) | 1999-02-05 | 2001-06-19 | Minimed Inc. | Analyte sensor and holter-type monitor system and method of using the same |
US6281006B1 (en) | 1998-08-24 | 2001-08-28 | Therasense, Inc. | Electrochemical affinity assay |
WO2000013003A1 (en) | 1998-08-26 | 2000-03-09 | Sensors For Medicine And Science, Inc. | Optical-based sensing devices |
DE19841173A1 (en) | 1998-09-09 | 2000-03-16 | Meier Bernd Horst | Method to transfer and measure gas or liquid volumes, e.g. volatile anaesthetics; involves using alternately rotating pistons to separate liquid volume in vessel formed as rotation body. |
US6740518B1 (en) | 1998-09-17 | 2004-05-25 | Clinical Micro Sensors, Inc. | Signal detection techniques for the detection of analytes |
US6254586B1 (en) | 1998-09-25 | 2001-07-03 | Minimed Inc. | Method and kit for supplying a fluid to a subcutaneous placement site |
US6201980B1 (en) | 1998-10-05 | 2001-03-13 | The Regents Of The University Of California | Implantable medical sensor system |
JP4469504B2 (en) | 1998-10-08 | 2010-05-26 | メドトロニック ミニメド インコーポレイテッド | Remote trait monitor system |
US6338790B1 (en) | 1998-10-08 | 2002-01-15 | Therasense, Inc. | Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator |
US6591125B1 (en) | 2000-06-27 | 2003-07-08 | Therasense, Inc. | Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator |
US6494879B2 (en) | 1998-10-15 | 2002-12-17 | Scimed Life Systems, Inc. | Treating urinary retention |
US6057377A (en) | 1998-10-30 | 2000-05-02 | Sandia Corporation | Molecular receptors in metal oxide sol-gel materials prepared via molecular imprinting |
US6164921A (en) | 1998-11-09 | 2000-12-26 | Moubayed; Ahmad Maher | Curvilinear peristaltic pump having insertable tubing assembly |
EP1130996B1 (en) | 1998-11-20 | 2005-04-13 | The University of Connecticut | Generic integrated implantable potentiostat telemetry unit for electrochemical sensors |
US20030099682A1 (en) | 1998-11-20 | 2003-05-29 | Francis Moussy | Apparatus and method for control of tissue/implant interactions |
CA2352571C (en) | 1998-12-02 | 2007-02-27 | Gary S. Sayler | In vivo biosensor apparatus and method of use |
WO2000038570A1 (en) | 1998-12-31 | 2000-07-06 | Ball Semiconductor, Inc. | Miniature implanted orthopedic sensors |
EP1139873B1 (en) | 1999-01-04 | 2008-09-17 | Terumo Kabushiki Kaisha | Body fluid collecting and detecting lancet assembly |
US6309384B1 (en) | 1999-02-01 | 2001-10-30 | Adiana, Inc. | Method and apparatus for tubal occlusion |
US6360888B1 (en) * | 1999-02-25 | 2002-03-26 | Minimed Inc. | Glucose sensor package system |
US6424847B1 (en) | 1999-02-25 | 2002-07-23 | Medtronic Minimed, Inc. | Glucose monitor calibration methods |
US6106494A (en) | 1999-03-19 | 2000-08-22 | Stryker Corporation | Self-contained fluid management pump system for surgical procedures |
WO2000059373A1 (en) | 1999-04-07 | 2000-10-12 | Spectrx, Inc. | Assay device for measuring characteristics of a fluid on a continual basis |
US6189536B1 (en) * | 1999-04-15 | 2001-02-20 | Medtronic Inc. | Method for protecting implantable devices |
JP2002542498A (en) | 1999-04-22 | 2002-12-10 | シグナス, インコーポレイテッド | Methods and devices for removing interfering species |
US6055456A (en) | 1999-04-29 | 2000-04-25 | Medtronic, Inc. | Single and multi-polar implantable lead for sacral nerve electrical stimulation |
US6254061B1 (en) * | 1999-04-30 | 2001-07-03 | Scimed Life Systems, Inc. | Medical suction valve |
WO2000066204A1 (en) | 1999-04-30 | 2000-11-09 | University Of Southern California | Implantable microbolus infusion pump |
US6465066B1 (en) | 1999-05-11 | 2002-10-15 | The Coca-Cola Company | Packaged potable liquid and packaging for potable liquid |
US6546268B1 (en) | 1999-06-02 | 2003-04-08 | Ball Semiconductor, Inc. | Glucose sensor |
JP4801301B2 (en) | 1999-06-18 | 2011-10-26 | アボット ダイアベティス ケア インコーポレイテッド | In vivo analyte sensor with limited mass transfer |
US7247138B2 (en) | 1999-07-01 | 2007-07-24 | Medtronic Minimed, Inc. | Reusable analyte sensor site and method of using the same |
US6368274B1 (en) | 1999-07-01 | 2002-04-09 | Medtronic Minimed, Inc. | Reusable analyte sensor site and method of using the same |
US6413393B1 (en) | 1999-07-07 | 2002-07-02 | Minimed, Inc. | Sensor including UV-absorbing polymer and method of manufacture |
US6310110B1 (en) | 1999-07-30 | 2001-10-30 | Michael A. Markowitz | Molecularly-imprinted material made by template-directed synthesis |
US6179806B1 (en) | 1999-08-05 | 2001-01-30 | Scimed Life Systems, Inc. | Self-occluding catheter |
US20020019330A1 (en) * | 1999-08-11 | 2002-02-14 | Richard Murray | Novel methods of diagnosis of angiogenesis, compositions, and methods of screening for angiogenesis modulators |
US6116394A (en) | 1999-08-13 | 2000-09-12 | Means Industries, Inc. | Overrunning coupling assembly |
US6471689B1 (en) | 1999-08-16 | 2002-10-29 | Thomas Jefferson University | Implantable drug delivery catheter system with capillary interface |
US6346583B1 (en) | 1999-08-25 | 2002-02-12 | General Electric Company | Polar solvent compatible polyethersiloxane elastomers |
US6343225B1 (en) | 1999-09-14 | 2002-01-29 | Implanted Biosystems, Inc. | Implantable glucose sensor |
US6251280B1 (en) | 1999-09-15 | 2001-06-26 | University Of Tennessee Research Corporation | Imprint-coating synthesis of selective functionalized ordered mesoporous sorbents for separation and sensors |
AT408182B (en) | 1999-09-17 | 2001-09-25 | Schaupp Lukas Dipl Ing Dr Tech | DEVICE FOR VIVO MEASURING SIZES IN LIVING ORGANISMS |
US6387324B1 (en) | 1999-09-30 | 2002-05-14 | Therox, Inc. | Apparatus and method for blood oxygenation |
JP2001104470A (en) | 1999-10-04 | 2001-04-17 | Seiko Instruments Inc | Valve device and valve system using the same |
US6541107B1 (en) | 1999-10-25 | 2003-04-01 | Dow Corning Corporation | Nanoporous silicone resins having low dielectric constants |
US6875386B1 (en) | 1999-11-17 | 2005-04-05 | Isense Corp. | Neovascularization promoting membrane for bioimplants |
US6670115B1 (en) | 1999-11-24 | 2003-12-30 | Biotronic Technologies, Inc. | Devices and methods for detecting analytes using electrosensor having capture reagent |
GB9928071D0 (en) | 1999-11-29 | 2000-01-26 | Polybiomed Ltd | Blood compatible medical articles |
US6520997B1 (en) | 1999-12-08 | 2003-02-18 | Baxter International Inc. | Porous three dimensional structure |
JP3852734B2 (en) | 1999-12-20 | 2006-12-06 | セイコーインスツル株式会社 | Pressure variable valve device and set pressure adjusting device for the valve device |
ATE373443T1 (en) | 2000-02-10 | 2007-10-15 | Medtronic Minimed Inc | ANALYTE SENSOR |
US6484045B1 (en) | 2000-02-10 | 2002-11-19 | Medtronic Minimed, Inc. | Analyte sensor and method of making the same |
US6895263B2 (en) | 2000-02-23 | 2005-05-17 | Medtronic Minimed, Inc. | Real time self-adjusting calibration algorithm |
US6303670B1 (en) | 2000-02-25 | 2001-10-16 | Nippon Paper Industries Co., Ltd. | Cellulose based coating composition curable with ultraviolet ray |
ATE499988T1 (en) | 2000-03-02 | 2011-03-15 | Microchips Inc | MICROMECHANICAL DEVICES AND METHODS FOR STORAGE AND SELECTIVE EXPOSURE OF CHEMICALS |
US6551496B1 (en) | 2000-03-03 | 2003-04-22 | Ysi Incorporated | Microstructured bilateral sensor |
US6498941B1 (en) | 2000-03-09 | 2002-12-24 | Advanced Cardiovascular Systems, Inc. | Catheter based probe and method of using same for detecting chemical analytes |
US6365670B1 (en) | 2000-03-10 | 2002-04-02 | Wacker Silicones Corporation | Organopolysiloxane gels for use in cosmetics |
US6405066B1 (en) | 2000-03-17 | 2002-06-11 | The Regents Of The University Of California | Implantable analyte sensor |
JP2003527599A (en) | 2000-03-17 | 2003-09-16 | エフ.ホフマン−ラ ロシュ アーゲー | Embedded analyte sensor |
AU2001263022A1 (en) | 2000-05-12 | 2001-11-26 | Therasense, Inc. | Electrodes with multilayer membranes and methods of using and making the electrodes |
US7181261B2 (en) | 2000-05-15 | 2007-02-20 | Silver James H | Implantable, retrievable, thrombus minimizing sensors |
US7769420B2 (en) | 2000-05-15 | 2010-08-03 | Silver James H | Sensors for detecting substances indicative of stroke, ischemia, or myocardial infarction |
US6442413B1 (en) | 2000-05-15 | 2002-08-27 | James H. Silver | Implantable sensor |
US6395325B1 (en) | 2000-05-16 | 2002-05-28 | Scimed Life Systems, Inc. | Porous membranes |
US6459917B1 (en) * | 2000-05-22 | 2002-10-01 | Ashok Gowda | Apparatus for access to interstitial fluid, blood, or blood plasma components |
US6569521B1 (en) | 2000-07-06 | 2003-05-27 | 3M Innovative Properties Company | Stretch releasing pressure sensitive adhesive tape and articles |
US6477392B1 (en) | 2000-07-14 | 2002-11-05 | Futrex Inc. | Calibration of near infrared quantitative measurement device using optical measurement cross-products |
US6795068B1 (en) | 2000-07-21 | 2004-09-21 | Sony Computer Entertainment Inc. | Prop input device and method for mapping an object from a two-dimensional camera image to a three-dimensional space for controlling action in a game program |
US6553244B2 (en) | 2000-08-18 | 2003-04-22 | Cygnus, Inc. | Analyte monitoring device alarm augmentation system |
US6633772B2 (en) | 2000-08-18 | 2003-10-14 | Cygnus, Inc. | Formulation and manipulation of databases of analyte and associated values |
DE60139262D1 (en) * | 2000-08-28 | 2009-08-27 | Disc Dynamics Inc | SYSTEM FOR RECONSTRUCTING JOINT SURFACES OF MAMMALS |
ES2267828T3 (en) * | 2000-10-10 | 2007-03-16 | Serono Genetics Institute S.A. | POLYMERS THAT ADSORBATE ON SURFACES AND THEIR USE TO TREAT HYDROPHOBIC OR HYDROPHILE SURFACES. |
US20060113231A1 (en) * | 2000-10-23 | 2006-06-01 | Abdul Malik | Sample pre-concentration tubes with sol-gel surface coatings and/or sol-gel monolithic beds |
ATE352333T1 (en) | 2000-11-09 | 2007-02-15 | Insulet Corp | DEVICE FOR TRANSCUTANEOUS DELIVERY OF MEDICATIONS |
JP2002174610A (en) | 2000-12-08 | 2002-06-21 | Nec Corp | Biosensor and liquid sample measurement method using biosensor |
EP1343557B1 (en) | 2000-12-11 | 2004-09-22 | Christoph Miethke Gmbh & Co. KG | Hydrocephalus valve |
US6520937B2 (en) * | 2000-12-18 | 2003-02-18 | Scimed Life Systems, Inc. | Fluid injection device |
WO2005032400A2 (en) | 2003-10-06 | 2005-04-14 | Nicast Ltd. | Method and apparatus for coating medical implants |
US6642015B2 (en) | 2000-12-29 | 2003-11-04 | Minimed Inc. | Hydrophilic polymeric material for coating biosensors |
WO2002053193A2 (en) | 2001-01-02 | 2002-07-11 | The Charles Stark Draper Laboratory, Inc. | Tissue engineering of three-dimensional vascularized using microfabricated polymer assembly technology |
US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
US6547839B2 (en) | 2001-01-23 | 2003-04-15 | Skc Co., Ltd. | Method of making an electrochemical cell by the application of polysiloxane onto at least one of the cell components |
US6520477B2 (en) * | 2001-02-01 | 2003-02-18 | William Trimmer | Micro pump |
US7014610B2 (en) | 2001-02-09 | 2006-03-21 | Medtronic, Inc. | Echogenic devices and methods of making and using such devices |
WO2002064027A2 (en) | 2001-02-15 | 2002-08-22 | The Regents Of The University Of California | Membrane and electrode structure for implantable sensor |
EP1381408A4 (en) | 2001-02-22 | 2007-06-13 | Insulet Corp | Modular infusion device and method |
WO2002072167A1 (en) | 2001-03-13 | 2002-09-19 | Implant Sciences Corporation. | Drug eluting encapsulated stent |
US6952603B2 (en) | 2001-03-16 | 2005-10-04 | Roche Diagnostics Operations, Inc. | Subcutaneous analyte sensor |
US7288085B2 (en) | 2001-04-10 | 2007-10-30 | Medtronic, Inc. | Permanent magnet solenoid pump for an implantable therapeutic substance delivery device |
US6454710B1 (en) | 2001-04-11 | 2002-09-24 | Motorola, Inc. | Devices and methods for monitoring an analyte |
US6574490B2 (en) | 2001-04-11 | 2003-06-03 | Rio Grande Medical Technologies, Inc. | System for non-invasive measurement of glucose in humans |
US6528584B2 (en) | 2001-04-12 | 2003-03-04 | The University Of Akron | Multi-component polymeric networks containing poly(ethylene glycol) |
US7167734B2 (en) | 2001-04-13 | 2007-01-23 | Abbott Laboratories | Method for optical measurements of tissue to determine disease state or concentration of an analyte |
DE10119036C1 (en) | 2001-04-18 | 2002-12-12 | Disetronic Licensing Ag | Immersion sensor for measuring the concentration of an analyte using an oxidase |
US20020162792A1 (en) | 2001-05-01 | 2002-11-07 | Zepf Robert F. | Polymer membrane meshes |
US6613379B2 (en) | 2001-05-08 | 2003-09-02 | Isense Corp. | Implantable analyte sensor |
US7029689B2 (en) | 2001-05-10 | 2006-04-18 | Georgia Tech Research Corporation | Tubular construct for implantation |
US6932894B2 (en) | 2001-05-15 | 2005-08-23 | Therasense, Inc. | Biosensor membranes composed of polymers containing heterocyclic nitrogens |
US20040023253A1 (en) * | 2001-06-11 | 2004-02-05 | Sandeep Kunwar | Device structure for closely spaced electrodes |
AU2002363627A1 (en) | 2001-06-11 | 2003-05-26 | Genorx, Inc. | Electronic detection of biological molecules using thin layers |
US6793632B2 (en) | 2001-06-12 | 2004-09-21 | Lifescan, Inc. | Percutaneous biological fluid constituent sampling and measurement devices and methods |
US6501976B1 (en) | 2001-06-12 | 2002-12-31 | Lifescan, Inc. | Percutaneous biological fluid sampling and analyte measurement devices and methods |
US6837988B2 (en) | 2001-06-12 | 2005-01-04 | Lifescan, Inc. | Biological fluid sampling and analyte measurement devices and methods |
US6802827B2 (en) * | 2001-06-26 | 2004-10-12 | Stig O. Andersson | Hypodermic implant device |
EP1399135B1 (en) | 2001-06-28 | 2004-12-29 | Microchips, Inc. | Methods for hermetically sealing microchip reservoir devices |
DE10296998T5 (en) * | 2001-07-24 | 2004-05-27 | Nec Corp. | Enzyme electrode and method of making the same |
US6702857B2 (en) | 2001-07-27 | 2004-03-09 | Dexcom, Inc. | Membrane for use with implantable devices |
US20030032874A1 (en) * | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
US6913626B2 (en) * | 2001-08-14 | 2005-07-05 | Mcghan Jim J. | Medical implant having bioabsorbable textured surface |
US6986739B2 (en) | 2001-08-23 | 2006-01-17 | Sciperio, Inc. | Architecture tool and methods of use |
US6663615B1 (en) | 2001-09-04 | 2003-12-16 | The Ohio State University | Dual stage microvalve and method of use |
US6595756B2 (en) | 2001-09-07 | 2003-07-22 | Medtronic Minimed, Inc. | Electronic control system and process for electromagnetic pump |
US6997921B2 (en) | 2001-09-07 | 2006-02-14 | Medtronic Minimed, Inc. | Infusion device and driving mechanism for same |
US6770067B2 (en) | 2001-09-07 | 2004-08-03 | Medtronic Minimed, Inc. | Infusion device and driving mechanism for same |
US7025760B2 (en) | 2001-09-07 | 2006-04-11 | Medtronic Minimed, Inc. | Method and system for non-vascular sensor implantation |
US7332330B2 (en) | 2001-09-11 | 2008-02-19 | Renamed Biologics, Inc. | Device for maintaining vascularization near an implant |
US6802957B2 (en) | 2001-09-28 | 2004-10-12 | Marine Biological Laboratory | Self-referencing enzyme-based microsensor and method of use |
US6809507B2 (en) | 2001-10-23 | 2004-10-26 | Medtronic Minimed, Inc. | Implantable sensor electrodes and electronic circuitry |
US7097775B2 (en) | 2001-10-26 | 2006-08-29 | Second Sight Medical Products, Inc. | Coated microfluidic delivery system |
US6989891B2 (en) * | 2001-11-08 | 2006-01-24 | Optiscan Biomedical Corporation | Device and method for in vitro determination of analyte concentrations within body fluids |
US7061593B2 (en) | 2001-11-08 | 2006-06-13 | Optiscan Biomedical Corp. | Device and method for in vitro determination of analyte concentrations within body fluids |
US6705833B2 (en) | 2001-11-15 | 2004-03-16 | Hewlett-Packard Development Company, L.P. | Airflow flapper valve |
US6814845B2 (en) | 2001-11-21 | 2004-11-09 | University Of Kansas | Method for depositing an enzyme on an electrically conductive substrate |
US20040030294A1 (en) * | 2001-11-28 | 2004-02-12 | Mahurkar Sakharam D. | Retractable needle single use safety syringe |
US20050101841A9 (en) | 2001-12-04 | 2005-05-12 | Kimberly-Clark Worldwide, Inc. | Healthcare networks with biosensors |
AU2002358128A1 (en) | 2001-12-17 | 2003-06-30 | Danfoss A/S | Method and device for monitoring analyte concentration by optical detection |
US6872927B2 (en) | 2001-12-26 | 2005-03-29 | Lambda Technologies, Inc. | Systems and methods for processing pathogen-contaminated mail pieces |
US7018336B2 (en) | 2001-12-27 | 2006-03-28 | Medtronic Minimed, Inc. | Implantable sensor flush sleeve |
WO2003061475A1 (en) | 2002-01-23 | 2003-07-31 | Danfoss A/S | Method and device for monitoring analyte concentration by use of differential osmotic pressure measurement |
US20030181794A1 (en) | 2002-01-29 | 2003-09-25 | Rini Christopher J. | Implantable sensor housing, sensor unit and methods for forming and using the same |
US10022078B2 (en) | 2004-07-13 | 2018-07-17 | Dexcom, Inc. | Analyte sensor |
US7828728B2 (en) | 2003-07-25 | 2010-11-09 | Dexcom, Inc. | Analyte sensor |
US8364229B2 (en) | 2003-07-25 | 2013-01-29 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US7613491B2 (en) | 2002-05-22 | 2009-11-03 | Dexcom, Inc. | Silicone based membranes for use in implantable glucose sensors |
US8260393B2 (en) | 2003-07-25 | 2012-09-04 | Dexcom, Inc. | Systems and methods for replacing signal data artifacts in a glucose sensor data stream |
FR2836047B1 (en) | 2002-02-21 | 2004-04-02 | Henri Mehier | FACILITY FOR DELIVERING CALORIES IN ALL OR PART OF A HUMAN OR ANIMAL CELLULAR FABRIC |
US6936006B2 (en) | 2002-03-22 | 2005-08-30 | Novo Nordisk, A/S | Atraumatic insertion of a subcutaneous device |
CA2480550C (en) | 2002-03-22 | 2011-07-12 | Cygnus, Inc. | Improving performance of an analyte monitoring device |
US7863038B2 (en) * | 2002-03-29 | 2011-01-04 | Board Of Regents, The University Of Texas System | Implantable biosensor from stratified nanostructured membranes |
JP2005522692A (en) | 2002-04-05 | 2005-07-28 | パワーザイム,インコーポレイテッド | Analyte sensor |
US20070227907A1 (en) | 2006-04-04 | 2007-10-04 | Rajiv Shah | Methods and materials for controlling the electrochemistry of analyte sensors |
US7153265B2 (en) | 2002-04-22 | 2006-12-26 | Medtronic Minimed, Inc. | Anti-inflammatory biosensor for reduced biofouling and enhanced sensor performance |
US7813780B2 (en) | 2005-12-13 | 2010-10-12 | Medtronic Minimed, Inc. | Biosensors and methods for making and using them |
FI118172B (en) | 2002-04-22 | 2007-08-15 | Inion Ltd | Surgical implant |
US6960192B1 (en) | 2002-04-23 | 2005-11-01 | Insulet Corporation | Transcutaneous fluid delivery system |
US7008979B2 (en) | 2002-04-30 | 2006-03-07 | Hydromer, Inc. | Coating composition for multiple hydrophilic applications |
US7166235B2 (en) | 2002-05-09 | 2007-01-23 | The Procter & Gamble Company | Compositions comprising anionic functionalized polyorganosiloxanes for hydrophobically modifying surfaces and enhancing delivery of active agents to surfaces treated therewith |
DE10393059D2 (en) | 2002-05-09 | 2005-05-04 | Hemoteq Gmbh | Compounds and methods for the hemocompatible coating of surfaces |
US6801041B2 (en) | 2002-05-14 | 2004-10-05 | Abbott Laboratories | Sensor having electrode for determining the rate of flow of a fluid |
US7226978B2 (en) | 2002-05-22 | 2007-06-05 | Dexcom, Inc. | Techniques to improve polyurethane membranes for implantable glucose sensors |
US20060258761A1 (en) | 2002-05-22 | 2006-11-16 | Robert Boock | Silicone based membranes for use in implantable glucose sensors |
AU2003240018A1 (en) | 2002-05-31 | 2003-12-19 | Dow Corning Toray Silicone Co., Ltd. | Cartridge for moisture-curable sealant |
US20030225324A1 (en) | 2002-06-03 | 2003-12-04 | Anderson Edward J. | Noninvasive detection of a physiologic Parameter within a body tissue of a patient |
US8996090B2 (en) * | 2002-06-03 | 2015-03-31 | Exostat Medical, Inc. | Noninvasive detection of a physiologic parameter within a body tissue of a patient |
EP1542743A1 (en) * | 2002-07-09 | 2005-06-22 | Gambro Lundia AB | An infusion device for medical use |
US20040063167A1 (en) | 2002-07-12 | 2004-04-01 | Peter Kaastrup | Minimising calibration problems of in vivo glucose sensors |
US20040010207A1 (en) * | 2002-07-15 | 2004-01-15 | Flaherty J. Christopher | Self-contained, automatic transcutaneous physiologic sensing system |
US7070591B2 (en) | 2002-09-17 | 2006-07-04 | Transoma Medical, Inc. | Vascular access port with physiological sensor |
US7150741B2 (en) | 2002-09-20 | 2006-12-19 | Advanced Neuromodulation Systems, Inc. | Programmable dose control module |
US6880564B2 (en) | 2002-09-20 | 2005-04-19 | Advanced Neuromodulation Systems, Inc. | Dosage control apparatus |
US8303511B2 (en) | 2002-09-26 | 2012-11-06 | Pacesetter, Inc. | Implantable pressure transducer system optimized for reduced thrombosis effect |
US6770729B2 (en) * | 2002-09-30 | 2004-08-03 | Medtronic Minimed, Inc. | Polymer compositions containing bioactive agents and methods for their use |
WO2004034032A2 (en) | 2002-10-11 | 2004-04-22 | Case Western Reserve University | Sliver type autonomous biosensors |
US20040074785A1 (en) | 2002-10-18 | 2004-04-22 | Holker James D. | Analyte sensors and methods for making them |
US7087017B2 (en) | 2002-10-31 | 2006-08-08 | Medtronic, Inc. | Atraumatic sensor lead assemblies |
WO2004044012A1 (en) | 2002-11-12 | 2004-05-27 | The Polymer Technology Group Incorporated | Control of polymer surface molecular architecture via amphipathic endgroups |
US7228160B2 (en) | 2002-11-13 | 2007-06-05 | Sorenson Medical, Inc. | System, apparatus and method for inferring glucose levels within the peritoneum with implantable sensors |
US20050032246A1 (en) * | 2002-11-14 | 2005-02-10 | Mcmaster University | Method of immobilizing membrane-associated molecules |
US20040120848A1 (en) | 2002-12-20 | 2004-06-24 | Maria Teodorczyk | Method for manufacturing a sterilized and calibrated biosensor-based medical device |
US6932584B2 (en) | 2002-12-26 | 2005-08-23 | Medtronic Minimed, Inc. | Infusion device and driving mechanism and process for same with actuator for multiple infusion uses |
US7255690B2 (en) | 2002-12-26 | 2007-08-14 | Medtronic Minimed, Inc. | Infusion device having piston operated driving mechanism and positive pressure reservoir |
US7120483B2 (en) | 2003-01-13 | 2006-10-10 | Isense Corporation | Methods for analyte sensing and measurement |
US6965791B1 (en) | 2003-03-26 | 2005-11-15 | Sorenson Medical, Inc. | Implantable biosensor system, apparatus and method |
US7134999B2 (en) | 2003-04-04 | 2006-11-14 | Dexcom, Inc. | Optimized sensor geometry for an implantable glucose sensor |
US7279174B2 (en) * | 2003-05-08 | 2007-10-09 | Advanced Cardiovascular Systems, Inc. | Stent coatings comprising hydrophilic additives |
EP1982772A1 (en) | 2003-05-16 | 2008-10-22 | Cinvention Ag | Bio-compatible coated medical implants |
US7875293B2 (en) | 2003-05-21 | 2011-01-25 | Dexcom, Inc. | Biointerface membranes incorporating bioactive agents |
US7687586B2 (en) | 2003-05-21 | 2010-03-30 | Isense Corporation | Biosensor membrane material |
US6789634B1 (en) | 2003-05-28 | 2004-09-14 | Smith International, Inc | Self-lubricating elastomeric seal with polarized graphite |
US20040254433A1 (en) | 2003-06-12 | 2004-12-16 | Bandis Steven D. | Sensor introducer system, apparatus and method |
US20050118344A1 (en) | 2003-12-01 | 2005-06-02 | Pacetti Stephen D. | Temperature controlled crimping |
US20050051427A1 (en) | 2003-07-23 | 2005-03-10 | Brauker James H. | Rolled electrode array and its method for manufacture |
WO2005012873A2 (en) | 2003-07-25 | 2005-02-10 | Dexcom, Inc. | Electrode systems for electrochemical sensors |
US20050176136A1 (en) | 2003-11-19 | 2005-08-11 | Dexcom, Inc. | Afinity domain for analyte sensor |
US7366556B2 (en) | 2003-12-05 | 2008-04-29 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
EP1648298A4 (en) | 2003-07-25 | 2010-01-13 | Dexcom Inc | Oxygen enhancing membrane systems for implantable devices |
WO2007120442A2 (en) | 2003-07-25 | 2007-10-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
WO2005019795A2 (en) | 2003-07-25 | 2005-03-03 | Dexcom, Inc. | Electrochemical sensors including electrode systems with increased oxygen generation |
WO2005012871A2 (en) | 2003-07-25 | 2005-02-10 | Dexcom, Inc. | Increasing bias for oxygen production in an electrode system |
US6931327B2 (en) | 2003-08-01 | 2005-08-16 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US7591801B2 (en) | 2004-02-26 | 2009-09-22 | Dexcom, Inc. | Integrated delivery device for continuous glucose sensor |
US7519408B2 (en) | 2003-11-19 | 2009-04-14 | Dexcom, Inc. | Integrated receiver for continuous analyte sensor |
US7287043B2 (en) | 2003-08-21 | 2007-10-23 | International Business Machines Corporation | System and method for asynchronous data replication without persistence for distributed computing |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
US7723099B2 (en) | 2003-09-10 | 2010-05-25 | Abbott Point Of Care Inc. | Immunoassay device with immuno-reference electrode |
US7361155B2 (en) | 2003-09-16 | 2008-04-22 | Therafuse, Inc. | Compensating liquid delivery system and method |
US7433727B2 (en) | 2003-09-24 | 2008-10-07 | Legacy Good Samaritan Hospital And Medical Center | Implantable biosensor |
WO2005032362A2 (en) * | 2003-09-30 | 2005-04-14 | Roche Diagnostics Gmbh | Sensor with increaseed biocompatibility |
US20050090607A1 (en) | 2003-10-28 | 2005-04-28 | Dexcom, Inc. | Silicone composition for biocompatible membrane |
ES2327741T3 (en) | 2003-10-31 | 2009-11-03 | Lifescan Scotland Ltd | A METHOD FOR REDUCING INTERFERENCES IN AN ELECTROCHEMICAL SENSOR USING TWO DIFFERENT APPLIED POTENTIALS. |
US7655119B2 (en) * | 2003-10-31 | 2010-02-02 | Lifescan Scotland Limited | Meter for use in an improved method of reducing interferences in an electrochemical sensor using two different applied potentials |
US7299082B2 (en) | 2003-10-31 | 2007-11-20 | Abbott Diabetes Care, Inc. | Method of calibrating an analyte-measurement device, and associated methods, devices and systems |
US20090012376A1 (en) | 2003-11-03 | 2009-01-08 | Children's Medical Center Corporation | Continuous Analyte Monitor and Method of Using Same |
US20050152941A1 (en) | 2003-11-20 | 2005-07-14 | Angiotech International Ag | Soft tissue implants and anti-scarring agents |
EP2239566B1 (en) | 2003-12-05 | 2014-04-23 | DexCom, Inc. | Calibration techniques for a continuous analyte sensor |
WO2005057173A2 (en) | 2003-12-08 | 2005-06-23 | Dexcom, Inc. | Systems and methods for improving electrochemical analyte sensors |
EP3263032B1 (en) | 2003-12-09 | 2024-01-24 | Dexcom, Inc. | Signal processing for continuous analyte sensor |
FR2864449A1 (en) | 2003-12-29 | 2005-07-01 | Ela Medical Sa | ACTIVE IMPLANTABLE MEDICAL DEVICE, IN PARTICULAR A CARDIAC STIMULATOR, WITH IMPROVED MANAGEMENT OF AUTOMATIC AAI / DDD MODE SWITCHING IN THE PRESENCE OF PAROXYSTIC BAV |
EP1711548A1 (en) | 2004-01-08 | 2006-10-18 | Dutch Polymer Institute | Polyurethanes, polyurethaneureas and polyureas and use thereof |
US20050182451A1 (en) | 2004-01-12 | 2005-08-18 | Adam Griffin | Implantable device with improved radio frequency capabilities |
US7637868B2 (en) | 2004-01-12 | 2009-12-29 | Dexcom, Inc. | Composite material for implantable device |
US7699964B2 (en) | 2004-02-09 | 2010-04-20 | Abbott Diabetes Care Inc. | Membrane suitable for use in an analyte sensor, analyte sensor, and associated method |
WO2005079257A2 (en) | 2004-02-12 | 2005-09-01 | Dexcom, Inc. | Biointerface with macro- and micro- architecture |
CN101189271A (en) | 2004-02-13 | 2008-05-28 | 北卡罗来纳大学查珀尔希尔分校 | Functional materials and novel methods for the fabrication of microfluidic devices |
US20050197554A1 (en) | 2004-02-26 | 2005-09-08 | Michael Polcha | Composite thin-film glucose sensor |
SG133420A1 (en) | 2005-12-13 | 2007-07-30 | Merlin Md Pte Ltd | An endovascular device with membrane having permanently attached agents |
US8277713B2 (en) | 2004-05-03 | 2012-10-02 | Dexcom, Inc. | Implantable analyte sensor |
US20050245799A1 (en) | 2004-05-03 | 2005-11-03 | Dexcom, Inc. | Implantable analyte sensor |
JP4799557B2 (en) | 2004-06-09 | 2011-10-26 | ベクトン・ディキンソン・アンド・カンパニー | Multi-sample sensor |
US20060015020A1 (en) * | 2004-07-06 | 2006-01-19 | Dexcom, Inc. | Systems and methods for manufacture of an analyte-measuring device including a membrane system |
US7246551B2 (en) * | 2004-07-09 | 2007-07-24 | Protedyne Corporation | Liquid handling device with surface features at a seal |
US7640048B2 (en) | 2004-07-13 | 2009-12-29 | Dexcom, Inc. | Analyte sensor |
US7783333B2 (en) * | 2004-07-13 | 2010-08-24 | Dexcom, Inc. | Transcutaneous medical device with variable stiffness |
US20060016700A1 (en) * | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
WO2006018425A2 (en) | 2004-08-16 | 2006-02-23 | Novo Nordisk A/S | Multiphase biocompatible semi-permeable membrane for biosensors |
US7534330B2 (en) | 2004-08-24 | 2009-05-19 | University Of South Florida | Epoxy enhanced polymer membrane to increase durability of biosensors |
US7244443B2 (en) | 2004-08-31 | 2007-07-17 | Advanced Cardiovascular Systems, Inc. | Polymers of fluorinated monomers and hydrophilic monomers |
US7468033B2 (en) | 2004-09-08 | 2008-12-23 | Medtronic Minimed, Inc. | Blood contacting sensor |
US7608042B2 (en) | 2004-09-29 | 2009-10-27 | Intellidx, Inc. | Blood monitoring system |
US9011831B2 (en) | 2004-09-30 | 2015-04-21 | Advanced Cardiovascular Systems, Inc. | Methacrylate copolymers for medical devices |
US20060094945A1 (en) | 2004-10-28 | 2006-05-04 | Sontra Medical Corporation | System and method for analyte sampling and analysis |
CA2586927A1 (en) | 2004-11-09 | 2006-05-18 | Angiotech Biocoatings Corp. | Antimicrobial needle coating for extended infusion |
CN100367906C (en) | 2004-12-08 | 2008-02-13 | 圣美迪诺医疗科技(湖州)有限公司 | Endermic implantating biological sensors |
US7604818B2 (en) | 2004-12-22 | 2009-10-20 | Advanced Cardiovascular Systems, Inc. | Polymers of fluorinated monomers and hydrocarbon monomers |
KR20070104574A (en) | 2004-12-30 | 2007-10-26 | 신벤션 아게 | Combination comprising an agent providing a signal, an implant material and a drug |
US20060171980A1 (en) | 2005-02-01 | 2006-08-03 | Helmus Michael N | Implantable or insertable medical devices having optimal surface energy |
US7364562B2 (en) | 2005-10-06 | 2008-04-29 | Optiscan Biomedical Corp. | Anti-clotting apparatus and methods for fluid handling system |
US7241586B2 (en) | 2005-02-17 | 2007-07-10 | Medtronic Minimed, Inc. | Polypeptide formulations and methods for making, using and characterizing them |
US8744546B2 (en) | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
US20060252027A1 (en) | 2005-05-05 | 2006-11-09 | Petisce James R | Cellulosic-based resistance domain for an analyte sensor |
WO2006110193A2 (en) | 2005-04-08 | 2006-10-19 | Dexcom, Inc. | Cellulosic-based interference domain for an analyte sensor |
JP5022621B2 (en) * | 2005-04-27 | 2012-09-12 | 三星エスディアイ株式会社 | Cylindrical lithium secondary battery |
US20060253085A1 (en) | 2005-05-06 | 2006-11-09 | Medtronic Minimed, Inc. | Dual insertion set |
EP1885870A1 (en) | 2005-05-17 | 2008-02-13 | Radiometer Medical ApS | Enzyme sensor including a water-containing spacer layer |
US20060263839A1 (en) | 2005-05-17 | 2006-11-23 | Isense Corporation | Combined drug delivery and analyte sensor apparatus |
JP4763777B2 (en) | 2005-05-17 | 2011-08-31 | ラジオメーター・メディカル・アー・ペー・エス | Enzyme sensor comprising a cover membrane layer coated with a hydrophilic polymer |
US20060275859A1 (en) | 2005-05-17 | 2006-12-07 | Kjaer Thomas | Enzyme sensor including a water-containing spacer layer |
US20070129524A1 (en) | 2005-12-06 | 2007-06-07 | Sunkara Hari B | Thermoplastic polyurethanes comprising polytrimethylene ether soft segments |
WO2007084516A2 (en) | 2006-01-18 | 2007-07-26 | Dexcom, Inc. | Membranes for an analyte sensor |
CA2577760A1 (en) | 2006-02-27 | 2007-08-27 | Tyco Healthcare Group Lp | Pressurized dip coating system |
CA2630550A1 (en) | 2006-02-27 | 2007-09-07 | Edwards Lifesciences Corporation | Flux limiting membrane for intravenous amperometric biosensor |
US20070233013A1 (en) | 2006-03-31 | 2007-10-04 | Schoenberg Stephen J | Covers for tissue engaging members |
US8114023B2 (en) * | 2006-07-28 | 2012-02-14 | Legacy Emanuel Hospital & Health Center | Analyte sensing and response system |
US7871456B2 (en) | 2006-08-10 | 2011-01-18 | The Regents Of The University Of California | Membranes with controlled permeability to polar and apolar molecules in solution and methods of making same |
CA2701006C (en) | 2006-09-27 | 2016-07-12 | University Of Connecticut | Implantable biosensor and methods of use thereof |
EP2257794B1 (en) | 2008-03-28 | 2018-05-09 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
DE112015002303T5 (en) | 2014-05-16 | 2017-02-09 | Uchiyama Manufacturing Corp. | Method for producing a magnetic encoder |
-
2006
- 2006-04-14 US US11/404,417 patent/US7613491B2/en active Active
-
2009
- 2009-07-29 US US12/511,982 patent/US8064977B2/en active Active
-
2011
- 2011-10-20 US US13/277,997 patent/US8543184B2/en active Active
-
2013
- 2013-07-25 US US13/951,358 patent/US9549693B2/en active Active
-
2016
- 2016-12-13 US US15/377,443 patent/US20170086717A1/en not_active Abandoned
-
2017
- 2017-10-27 US US15/796,163 patent/US10052051B2/en active Active
-
2018
- 2018-07-18 US US16/039,178 patent/US11020026B2/en active Active
-
2021
- 2021-05-25 US US17/330,265 patent/US20210345916A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060020192A1 (en) * | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230218210A1 (en) * | 2015-12-30 | 2023-07-13 | Dexcom, Inc. | Transcutaneous analyte sensor systems and methods |
US11963796B1 (en) | 2017-04-29 | 2024-04-23 | Biolinq Incorporated | Heterogeneous integration of silicon-fabricated solid microneedle sensors and CMOS circuitry |
US11872055B2 (en) | 2020-07-29 | 2024-01-16 | Biolinq Incorporated | Continuous analyte monitoring system with microneedle array |
US12011294B2 (en) | 2020-07-29 | 2024-06-18 | Biolinq Incorporated | Continuous analyte monitoring system with microneedle array |
US11857344B2 (en) | 2021-05-08 | 2024-01-02 | Biolinq Incorporated | Fault detection for microneedle array based continuous analyte monitoring device |
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US20170086717A1 (en) | 2017-03-30 |
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